1.2.1 Circle of Willis

An anastomotic circle is formed around the optic chiasm between the anterior cerebral arteries (via the anterior communicating artery) and the posterior cerebral arteries (via the posterior communicating arteries).

1.2.2 Cerebral Venous Drainage

The superficial system of veins draining the cerebral cortex include the superior cerebral veins, middle cerebral veins, inferior cerebral veins, superior and inferior anastomotic veins. The superficial veins drain into the superior and inferior sagittal sinuses (Figure 1.4).

The deep veins include subependymal veins, the great cerebral vein, and medullary veins. The deep veins drain into the great cerebral vein and then to the straight or transverse sinuses.

The dural venous sinuses are valveless structures found between the periosteal and meningeal layer of the dura mater and drain into the internal jugular vein. The straight, superior, and inferior sagittal sinuses are found in the falx cerebri of the dura mater and converge at the confluence of sinuses. From here the transverse sinus, located bilaterally in the tentorium cerebelli, curves into the sigmoid sinus and then to the internal jugular vein, which exits at the jugular foramen. The great cerebral vein and the inferior sagittal sinus continue as the straight sinus.

The cavernous sinus is clinically relevant due to its vulnerability as a site of infection. It contains the internal carotid artery, abducens nerve, oculomotor nerve, trochlear nerve, and the ophthalmic and maxillary branches of the trigeminal nerve. The sinus is connected to the valveless facial vein via the superior ophthalmic vein, allowing reverse blood flow to the sinus, and is therefore a potential route of intracranial infection. The cavernous sinus also receives venous drainage from the central vein of the retina, the sphenoparietal sinus, the superficial middle cerebral vein, and the pterygoid plexus. These empty into the superior and inferior petrosal sinuses and, ultimately, into the internal jugular vein. The left and right cavernous sinuses are connected in the midline by the anterior and posterior intercavernous sinuses.

1.2.3 Lymphatics of the Brain

It has been a longstanding belief that the vertebrate brain does not contain a classic lymphatic drainage system. Instead, it was thought the brain has a “glymphatic system,” a perivascular pathway that allows cerebrospinal fluid (CSF) to recirculate through the brain interstitium along perivascular spaces near the cerebral arteries. This pathway was also thought to be responsible for the clearance of interstitial solutes along perivascular channels near the veins, mediated by astroglial water channels. However, recent findings have provided evidence of a functional lymphatic system in the brain, which acts to transport interstitial fluid (ISF) and solutes from the parenchyma to the deep cervical lymph nodes. The lymphatic system also helps maintain the water and ion balance of the ISF and allows communication with the immune system. The lymphatic vessels are associated with the superior sagittal and transverse sinus and the dural middle meningeal arteries. It is likely that the lymphatic system works in conjunction with other efflux pathways, such as via the dural arachnoid granulations.

1.6.1 Dura Mater

This layer is found underneath the bones and consists of the outer periosteal layer and the inner meningeal layer and in between houses the dural venous sinuses. The meningeal layer folds inward to form the dural reflections and forms compartments. These compartments are the falx cerebri, the tentorium cerebelli, the falx cerebelli (separates the cerebellar hemispheres), and the diaphragma sellae (allows the passage of the pituitary stalk). Blood collecting in between the skull and the outer periosteal layer is known as an extradural hematoma and usually occurs due to damage to the middle meningeal artery. A subdural hematoma occurs due to damage of the cerebral veins between the dura and the arachnoid mater.

1.6.2 Arachnoid Mater

The arachnoid mater consists of avascular connective tissue. Below it lies the subarachnoid space containing CSF, which re-enters the circulation via the dural venous sinuses through small projections called arachnoid granulations.

1.6.3 Pia Mater

This is a highly vascularized layer that adheres to the brain surface and follows the contours of the brain into the gyri of the cerebral hemispheres and the folia of the cerebellum. The pia mater and arachnoid mater are joined by connective tissue in the subarachnoid space and together are known as leptomeninges. There are compartments where the two are not in close approximation, resulting in naturally enlarged CSF filled pools called the subarachnoid cisterns.

1.7.1 Sympathetic Ganglia Supplying the Head and Neck: Cervical Ganglia

There are three cervical ganglia that supply the head and neck (the superior, middle, and inferior cervical ganglia). The superior ganglion is found posterior to the carotid artery and gives rise to a number of postganglionic nerves: the internal and external carotid nerves, the nerve to the pharyngeal plexus, the superior cardiac branch, and the gray rami communicantes. The middle ganglion may be absent, but when present is found anterior to the inferior thyroid artery. Its postganglionic fibers are the gray rami communicantes, the thyroid branches, and the middle cardiac branch. The inferior cervical ganglion is situated anteriorly to the C7 vertebra. Its branches are the gray rami communicantes, branches to the subclavian and vertebral arteries, and the inferior cardiac nerve. Damage to sympathetic fibers en route to the head and neck can lead to Horner’s syndrome, a condition presenting with partial ptosis of the upper eyelid, miosis (constricted pupil) and hemi-facial anhidrosis (absence of sweating).

1.7.2 Parasympathetic Ganglia Supplying the Head and Neck

The parasympathetic fibers supplying the head and neck are found in four brainstem nuclei associated with a cranial nerve. They synapse in a peripheral ganglion near the target viscera. There are four parasympathetic ganglia located within the head –ciliary, otic, pterygopalatine, and submandibular. They receive fibers from the oculomotor, facial, and glossopharyngeal nerves (the vagus nerve only innervates structures in the thorax and abdomen).

The ciliary ganglion is located within the bony orbit. Its preganglionic fibers are from the Edinger–Westphal nucleus, associated with the oculomotor nerve. Its postganglionic fibers leave the ganglion via the short ciliary nerves to innervate the sphincter pupillae and the ciliary muscles. Sympathetic nerves from the internal carotid plexus and sensory fibers from the nasocilary nerve pass through the ganglion without synapsing.

The pterygopalatine ganglion is located within the pterygopalatine fossa and is supplied by fibers from the superior salivatory nucleus (associated with the facial nerve). Its postganglionic fibers join branches of the maxillary nerve to supply the lacrimal gland, the nasopharynx, and the palate.

Sympathetic fibers from the internal carotid plexus and sensory branches from the maxillary nerve pass through the pterygopalatine ganglion without synapsing.

The submandibular ganglion is located inferiorly to the lingual nerve and is supplied by fibers from the superior salivatory nucleus. These fibers are carried within a branch of the facial nerve, the chorda tympani. This nerve travels along the lingual branch of the mandibular nerve to reach the ganglion and leaves the ganglion to the submandibular and sublingual glands. Sympathetic fibers from the facial artery plexus pass through the submandibular ganglion. They are thought to innervate glands in the base of the oral cavity.

The otic ganglion is located inferiorly to the foramen ovale within the infratemporal fossa. It is medial to the mandibular branch of the trigeminal nerve. The ganglion is supplied by fibers from the inferior salivatory nucleus (associated with the glossopharyngeal nerve). Parasympathetic fibers travel within the lesser petrosal nerve, a branch of the glossopharyngeal nerve, to reach the otic ganglion. The parasympathetic fibers travel along the auriculotemporal nerve (a branch of the mandibular division of the trigeminal nerve) to provide secretomotor innervation to the parotid gland. Sympathetic fibers from the superior cervical chain pass through the otic ganglion, where they travel with the middle meningeal artery to innervate the parotid gland.

1.10.1 Brodmann’s Map

The cerebral cortex can also be subdivided into 52 functional regions, numbered by the neuroanatomist Korbinian Brodmann based on cytological structure. The primary motor cortex (Brodmann area 4) is anterior to the central sulcus (Figure 1.10). It contains large neurons called Betz cells, which send axons to the spinal cord and is important for planning and execution of movements. The topographic map of the motor cortex is arranged with an “overrepresentation” of neurons responsible for complex motor behaviors (Figure 1.11). The premotor cortex (Brodmann area 6) also plays a role in planning movement; however, its function is less well understood. The supplementary motor area (Brodmann area 6) contributes to the control of movement. The primary somatosensory cortex (Brodmann areas 3, 2, and 1) is found in the parietal lobe, posterior to the central sulcus. It processes afferent somatosensory input and helps integrate sensory and motor information required for skilled movement. The primary visual cortex (Brodmann area 17) is at the occipital pole. The extra striate cortex is adjacent to the visual cortex and processes specific features of visual information. It can be separated into two streams. The ventral stream is from the primary visual cortex to the temporal lobe and is important for pattern and object recognition. The dorsal stream from the striate cortex into the parietal lobe is responsible for spatial recognition of motion and location. The primary auditory cortex is responsible for recognition of auditory stimuli and is in the lateral temporal lobe. Wernicke’s area (Brodmann area 22) is located in the superior temporal gyrus of the dominant cerebral hemi- sphere. It is important for comprehension of written and spoken language, and therefore any damage to this area leads to fluent but nonsensical speech. Broca’s area (Brodmann areas 44 and 45) is located in the dominant prefrontal cortex and is involved in language processing and speech production. Lesions in this region lead to expressive aphasia, where the patient retains comprehension but cannot create fluent speech.

Figure 1.11

Topographic map of the primary motor cortex.

1.10.2 Layers of The Cerebral Cortex

The cerebral neocortex is arranged in six layers. The outermost layer is the molecular layer (layer I), containing fibers that run parallel to the cortical surface with very few neurons. Layer II is the outer granular layer, containing small, rounded neurons. Below this is the outer pyramidal layer (layer III), containing pyramidal neurons. Next is the inner granular layer (layer IV), containing spiny stellate and pyramidal cells. It is a major input layer and receives specific sensory inputs from thalamocortical afferent fibers. The primary sensory cortex has a well-developed layer IV, but the output layers are less well developed. Layer IV is well developed in the primary visual cortex and contains the stria of Gennari, a band of myelinated axons that runs parallel to the surface of the cerebral cortex. The inner pyramidal later (layer V) contains many output neurons. The primary motor cortex has a very enlarged layer V containing large Betz cells, which send axons to the contralateral motor nuclei of cranial nerves and to the lower motor neurons in the ventral horn of the spinal cord. Finally, layer VI is the innermost, multiform layer containing morphologically heterogenous population of neurons and sends efferent fibers to the thalamus.

Certain parts of the cortex are arranged differently: the hippocampus has three layers and the cingulate gyrus has four to five layers.

1.10.3 Vascular Supply

The branches of the anterior, middle, and posterior cerebral arteries are responsible for the blood supply to the cerebrum. The venous drainage of the cerebrum is via cerebral veins that empty into the dural venous sinuses (Figure 1.4).

1.13.1 Basal Ganglia

The basal ganglia are situated at the base of the forebrain and top of the midbrain. They are a group of subcortical nuclei connected to the cerebral cortex, thalamus, and the brainstem. The basal ganglia are responsible for control of voluntary motor movements, procedural learning, cognition, and emotion. They con- sist of several distinct structures (Figure 1.14) and these include the caudate nucleus and putamen (together known as the neostriatum) separated by the internal capsule). The internal capsule is the site of the passage of many fibers including the efferent corticobulbar fibers, corticospinal fibers, efferent corticopontine fibers, and afferent thalamocortical fibers.

Figure 1.14

Cross-section of the basal ganglia.

The caudate receives inputs from the prefrontal cortex and the putamen receives inputs from the sensorimotor cortex. They send outputs to the external and internal globus pallidus and then to the thalamus and cerebral cortex, forming a subcortical loop. The internal segment projects to the motor areas of the thalamus and the medial nucleus of the thalamus. The external segment projects to the subthalamic nucleus (STN), which also projects to the internal globus pallidus.

The neostriatum also projects to the substantia nigra par compacta (SNPC), which contains dopaminergic neurons and to the pars reticulata, which contains mainly GABAergic neurons and is one of the output nuclei of the basal ganglia to the thalamus (alongside the internal globus pallidus) and plays a vital role in movement execution. The neostriatum is supplied by small branches of the middle and anterior cerebral arteries. The neostriatum and internal capsule are commonly affected in stroke. Damage to the internal capsule leads to contralateral weakness. The most affected region of the internal capsule is the genu, where corticospinal fibers to the head, neck, and part of the upper limb are located.

1.13.1.1 Connections of the Basal Ganglia

The striatum receives input from the cerebral cortex and the SNPC (Figure 1.15). The striatum sends inhibitory connections to the internal and external globus pallidus. The external region therefore disinhibits the STN, which then sends excitatory input to the internal globus pallidus. This sends inhibitory input to the thalamus, leading to inhibition of information flow to the cerebral cortex.

Figure 1.15

Basal ganglia connections.

The basal ganglia also project to the medial dorsal nucleus of the thalamus, which then projects to the prefrontal association cortex. This region is involved in higher cortical and executive function.

Parkinson’s disease results from degeneration of dopaminergic neurons of the SNPC and excessive inhibition of the thalamus. The SNPC projects to both direct and indirect pathways in the striatum. Due to the presence of two different types of dopamine receptors, the net effect is to excite the direct pathway and inhibit the indirect pathway. However, the loss of the neurons in Parkinson’s disease upsets the fine balance of these pathways and reduces excitation of the motor cortex, resulting in poverty of movement.

1.13.2 Thalamus

The thalamus is located in the forebrain and contains nuclei with connections to the cerebral cortex, the hippocampus, the mammillary bodies, and the fornix.

The thalamus is divided into three major nuclear groups (anterior, medial, and ventral) (Figure 1.16). The ventral group contains ascending somatosensory relays (ventroposterior nuclei) and relays from the cerebellum and basal ganglia (ventrolateral). It also contains the motor association areas (ventro-anterior nuclei). The lateral and medial geniculate nuclei are found posteriorly. The anterior group projects to the cingulate gyrus and receives input from the mammillary bodies of the hypothalamus. The medial nuclei and the pulvinar receive input from the cerebral cortex and form the cortico-thalamo-cortical relays, which project to areas of the association cortex. These are the prefrontal cortex and the temporal–parietal–occipital association cortex, which mainly receive input from the medial nuclei and the pulvinar, respectively.

Figure 1.16

Nuclei of the thalamus.

The thalamus is supplied by the posterior cerebral artery and branches of the posterior communicating artery. The thalamus is involved in learning, episodic memory, regulation of sleep, and wakefulness. Lesions in the anterior thalamus can lead to obstruction of the interventricular foramen of Monro and lesions in the posteriomedial thalamus can obstruct the third ventricle and cerebral aqueduct, leading to the development of hydrocephalus.

1.13.3 Cingulate Gyrus

The cingulate gyrus is situated above the corpus callosum (Figure 1.10). The anterior part relays signals between the right and left hemispheres and is involved in autonomic functions and cognitive processes such as reward behavior, empathy, and emotion. The posterior part becomes continuous with the most medial part of the temporal lobe, the parahippocampal gyrus. The cingulate gyrus is thought to be involved in retrieving episodic memory information. Dysfunction of this gyrus is found in schizophrenia and depression. Deep brain stimulation of the subgenual cortex of the gyrus is used to treat intractable depression. Output fibers are mainly to the parahippocampal gyrus and are linked by the cingulum, a white-matter tract.

1.13.4 Hippocampus

The hippocampus is a seahorse-shaped structure and the hippocampal formation refers to the hippocampus proper (Cornu Ammonis), the dentate gyrus, and the subiculum. It is found in the temporal lobe, medial to the inferior horn of the lateral ventricle.

The hippocampus has been studied extensively and is used as a model system for electrophysiological studies, particularly for investigating neural plasticity. Damage to the hippocampus is commonly seen in patients with dementia, particularly Alzheimer’s disease.

Hippocampal tissue is made up of layers and these include, from outer to inner: an external plexiform layer; a stratum oriens layer containing basal dendrites and basket cells; a pyramidal cell layer containing the primary cells of the hippocampus; a stratum radiatum layer; and the stratum lacunosum-moleculare layers containing the perforate pathway made up of pyramidal cell apical dendrites and afferent fibers from the entorhinal cortex. The external plexiform layer contains the alvear pathway, and this contains pyramidal cell axons through which information from the hippocampus is passed to the inferior horn of the lateral ventricle before reaching the entorhinal cortex. In addition, the hippocampus also contains distinct regions. The shape of the hippocampus has been described as similar to a seahorse or a ram’s horn (Cornu Ammonis). The abbreviation CA is used to name the different regions: CA1, CA2, CA3, and CA4 (Figure 1.17).

Figure 1.17

Cornu Ammonis axons of the hippocampus.

1.13.4.2 Hippocampal Inputs

The hippocampus receives information from the lateral perforate and medial perforate pathways in the entorhinal cortex (Figure 1.18), the prefrontal cortex, the anterior cingulate gyrus, the pre- mammillary region, and the reticular formation of the brainstem. It also receives input from the thalamus to field CA1 and from the serotonin, norepineph- rine, and dopamine systems. The medial septal nucleus sends cholinergic and γ-aminobutyric acid (GABA)-ergic inputs to the hippocampus.

Figure 1.18

Hippocampal connections.

The largest input and output pathway of the hippocampus is via the fornix, which connects it to other structures including the mammillary bodies of the hypothalamus, prefrontal cortex and the lateral septal area. The entorhinal cortex (part of the parahippocampal gyrus) receives output from the deeper layers of the hippocampus and gives input to the superficial layers.

The fornix has two branches: the precommissural and the postcommissural pathways. The former connects to the septal nuclei, preoptic nuclei, ventral striatum, orbital cortex, and anterior cingulate gyrus. The postcommissural branch connects to the anterior nucleus of the thalamus and mammillary bodies of the hypothalamus. In Korsakoff’s syndrome, these bodies are damaged and hence patients have trouble learning new memories. The anterior thalamic nuclei connect to the cingulate cortex, which connects back to the entorhinal cortex and creates the Papez circuit, which is involved in learning, memory, and emotion.

1.13.4.3 Hippocampus and Memory

Memory is the ability to acquire, store, and retrieve information and are formed through learning. The process of learning activates engram cells, a population of cells that have undergone cellular changes as a result of learning and when reactivated by the original stimulus leads to memory recall.

1.13.4.3.1 Spatial Memory

The hippocampus is well known to be involved in spatial memory and navigation. Within the hippocampus are found place cells, which contain information regarding the spatial context in which a memory took place in one specific location. These cells cluster in place fields and fire action potentials when an animal passes a certain location. Place-cell responses have been seen in the pyramidal cells of the hippocampus and the granule cells of the dentate gyrus. This is in contrast to the grid cells found in the entorhinal cortex, which generate a map of firing patterns covering entire regions. The spatial firing sequences appear to be stored in the hippocampus during exploration and can be retrieved at a later time. The dorsal hippocampus is responsible for spatial memory, verbal memory, and learning conceptual information, and there appear to be more place cells in the dorsal region. The ventral hippocampus functions in fear conditioning and affective processes.

1.13.4.3.2 Explicit Versus Implicit Memory

Declarative or explicit memories are available in the consciousness as semantic facts or episodic memories (Figure 1.19). The areas of the brain involved are the hippocampus, the neocortex, and the amygdala. Non-declarative memories, also known as implicit memories, are memories of skills, and rely on the basal ganglia and cerebellum. Short-term memories (seconds to minutes) are brief memories including working memory and rely heavily on the prefrontal cortex. These memories can be consolidated into long-term memory.

Figure 1.19

Declarative versus non-declarative memory.

Formation of explicit memory begins with consolidation and storage of encoded information in the hippocampus. Over time, certain memories can be transferred to the neocortex as general knowledge. The amygdala interacts with the hippocampus and neocortex to stabilize a memory and form new memories related to fear.

One of the earlier findings of how the hippocampus impacts memory consolidation came from the study of Henry Molaison, a patient who had a bilateral temporal lobectomy to treat his epileptic seizures. The surgery led to deficits including an inability to complete tasks that required long-term episodic memory and an inability to create new long-term memories. His spatial orientation was also severely affected. His long-term memory of events many years before the accident was largely intact and his procedural memory and intelligence were unaffected. This showed that the medial temporal lobe containing the hippocampus is important for declarative but not procedural memory consolidation.

Neurophysiological theories of synaptic plasticity based on the cellular models that underpin synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD) (see Chapter 5 for further details) can be used to explain the neural basis of learning and memory. Donald Hebb was the first to postulate that activation or inactivation of extant synaptic contacts depends on the synchronous impulse activity of pre- and postsynaptic nerve cells.

One of the most fascinating features of the hippocampus is its capacity for plasticity. Action potentials travel down the Schaffer collaterals and stimulate the release of glutamate into the synaptic cleft, which stimulates the α-amino-3-hydroxy-5-methyl-4-isoxazo-lepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Once the AMPA receptors open, sodium travels into the postsynaptic membrane and elicits a membrane depolarization. With a large enough stimulation, a large amount of glutamate will be released, allowing a large membrane depolarization that removes the magnesium block typically seen at the NMDA receptor. This allows both sodium and calcium to enter the postsynaptic membrane. The calcium activates protein kinases and stimulates a cascade of short- and long-term changes. In the short term, there is insertion of AMPA receptors (Figure 1.20), and in the long term there are changes in transcription factors and increased protein translation. This forms the basis of LTP.

Figure 1.20

Long-term potentiation.

On the contrary, LTD is induced by prolonged low-frequency stimulation, which leads to prolonged calcium activation of phosphatase enzymes and an eventual removal of AMPA receptors and pruning of spines.

1.13.4.3.3 Implicit Memory

Implicit memory involves several different brain regions. Classical conditioning involves various sensory and motor systems. Operant conditioning involves the striatum and cerebellum and fear conditioning involves the amygdala.

Classic (Pavlov) conditioning refers to learning that occurs when a neutral stimulus becomes associated with a stimulus that naturally produces a behavior. It was first observed by the Russian physiologist Ivan Pavlov, who exposed dogs to sounds (neutral stimulus) immediately before receiving food (natural stimulus producing behavior). Initially, the dogs began to salivate only when they saw the food; however, later, the dogs learned to associate the sound with the food and began salivating as they heard the sound. The food is the unconditioned stimulus as it naturally leads to a behavior. The conditioned stimulus is the neutral tone, which upon repeated presentation leads to the same behavior as the unconditioned stimulus. Classic conditioning involves enhanced synaptic strength due to presynaptic facilitation, where there is increased release of neurotransmitters from the presynaptic cells under the action of an additional neuron.

Habituation is a type of non-associative learning where a repetitive stimulus leads to a decrement in the response intensity. Sensitization is the increment in response intensity in response to a stimulus. Experiments performed in the sea slug, Aplysia californica, by Eric Kandel were crucial in establishing the importance of synaptic changes to learning and memory. It was demonstrated that upon stimulation of the siphon receptors, the motor neuron is activated directly or indirectly through the excitatory interneuron as the gill is withdrawn. However, with repeated stimulation, there is reduced release of synaptic transmitters from the sensory neurons and therefore there is less withdrawal of the gill (habituation). This would typically occur when an animal repeatedly encounters a harmless stimulus. However, when the animal encounters a harmful stimulus, a vigorous response occurs to not only the harmful stimulus but also the harmless stimulus (sensitization). When the head or tail of the Aplysia is stimulated by an electric shock, there is activation of the facilitatory interneurons. These synapse with the sensory neurons of the head, and there is increased transmitter release leading to excitation of the excitatory interneurons and the motor neurons to the gill (Figure 1.21). Dishabituation refers to the restoration of a full-strength response that was weakened by habituation.

Figure 1.21

Aplysia californica experiments performed to demonstrate habituation and sensitization.

Operant conditioning, is learning that occurs based on the consequences of behavior (e.g. reinforcement or punishment). This is a voluntary behavioral response and according to the law of effect, the behavior is strengthened or weakened by the learner based on their desired result. The early studies on operant conditioning were performed by Edward Thorndike and B. F. Skinner. The “Skinner box” was designed to study the principles of animal behavior in a controlled environment.

1.13.5 Amygdala

The amygdala is one of two almond-shaped clusters of nuclei found medially within the temporal lobe and is responsible for emotions such as fear and aggression. Emotion is a subjective state and consists of a physical response involving the autonomic motor and endocrine systems. It also requires conscious registration, and this involves both the cerebral cortex and the amygdala. The amygdala is also involved in memory formation, reward processing, and decision making.

1.13.6 Nucleus Accumbens

The nucleus accumbens is part of the striatum. It receives input from the orbitofrontal cortex, the cingulate cortex, and the amygdala and is involved in emotion and motivation.

1.13.7 Prefrontal Cortex

The prefrontal cortex is located in the frontal lobe and is implicated in personality development, decision making, and reasoning. Its role was discovered from the symp- toms and signs that Phineas Gage (an American railroad construction worker) developed following an accident that involved a rod being driven into his brain resulting in irreversible damage to his frontal lobe.

The medial part of the prefrontal cortex connects with the amygdala, the hippocampus, and the temporal lobe. The lateral part connects to the basal ganglia, the premotor cortex, the supplemental motor area, the thalamus, and the cingulate cortex. The orbitofrontal region forms connections with the amygdala, the medial part of the thalamus, the hypothalamus, and the basal ganglia.

1.13.8 Olfactory Bulb

The olfactory nerve projects to the olfactory bulb in the forebrain. The bulb is separated from the olfactory epithelium by the cribriform plate. It contains neurons involved in olfaction and receives sensory input from axons of the olfactory receptor neurons in the olfactory epithelium and outputs to the mitral cell axons. It then sends olfactory information to the amygdala, the orbitofrontal cortex, and the hippocampus. It also receives information from the amygdala, the neocortex, the hippocampus, the locus coeruleus, and the substantia nigra.

The bulb is divided into the main and accessory parts. The main bulb connects to the amygdala via the piriform cortex of the primary olfactory cortex. Associative learning between certain odors and behaviors takes place in the amygdala. The accessory bulb forms a parallel pathway.

1.13.9 Hypothalamus

The hypothalamus is bordered by the optic chiasm anteriorly and the mammillary bodies posteriorly. The function of the hypothalamus is to maintain homeostasis. It links the nervous system to the endocrine system via the pituitary gland, which is located below it. It contains four regional groups of nuclei (Figure 1.22): the preoptic region (which contains the preoptic nucleus), the supraoptic region (which contains suprachiasmatic, supraoptic, paraventricular, and anterior nuclei), the tuberal region (which contains dorsomedial, ventromedial, arcuate, premammillary and lateral tuberal nuclei), and the mammillary region (which contains mammillary and posterior nuclei). The medial preoptic nucleus secretes gonadotropin-releasing hormone (GnRH), which is responsible for the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. The paraventricular and supraoptic nuclei both produce the peptide hormones and antidiuretic hormone (ADH). The paraventricular nucleus also releases thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and somatostatin. TRH is responsible for the formation and secretion of the thyroid-stimulating hormone (TSH) in the pituitary gland, which in turn regulates the production of thyroid hormones in the thyroid gland. TRH also stimulates the release of prolactin from the pituitary gland. Corticotropin-releasing hormone activates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Somatostatin regulates the endocrine and digestive systems. The anterior nucleus is involved in thermoregulation by stimulating the PNS, and causes hyperthermia if damaged. The suprachiasmatic nucleus regulates the circadian rhythm and pineal gland function. The ventromedial nuclei mediate satiety. The lateral nuclei mediate hunger via orexin neurons. The arcuate nuclei secrete prolactin, growth hormone releasing hormone (GHRH), and GnRH. Dorsomedial nuclei regulate blood pressure and heart rate. The posterior nuclei release vasopressin and are involved in thermoregulation via the SNS. The mammillary nuclei are involved in memory.

Figure 1.22

Hypothalamic nuclei.

1.17.1 Pons

The pons is found below the midbrain and above the medulla (Figure 1.25). It develops from the embryonic metencephalon. The pons is the site of origin for several cranial nerves (Figure 1.26).

Figure 1.25

Sagittal section of the brain demonstrating the medulla and pons.

Figure 1.26

Cranial nerves emerging from the pons and medulla.

The pons is connected to the cerebellum via the middle cerebellar peduncles. Underlying the cerebellum is the fourth ventricle. The angle formed at the junction of the pons, the medulla, and the cerebellum is the cerebellopontine angle. The floor of the fourth ventricle reveals some anatomical landmarks including the medial eminence at the midline, the facial colliculus (containing the abducens nucleus and the facial motor fibers), and the stria medullaris (a part of the epithalamus). The pons is comprised of the ventral pons containing the pontine nuclei (responsible for coordination of movement), corticospinal and corticobulbar tracts, and the dorsal pons (tegmentum), which forms part of the reticular formation responsible for arousal and attentiveness and which contains cranial nerves and the fourth ventricle.

1.17.2 Vascular Supply

The pons is supplied by the pontine artery (basilar artery branch), the superior cerebellar artery, and the anterior inferior cerebellar artery. The pons drains to the anterior pontomesencephalic vein, and then to the basal and cerebral veins. The inferior aspects drain into the inferior petrosal sinus, which drains into the internal jugular veins.

1.18.1 Vascular Supply

The vessels that supply the medulla include: the anterior spinal artery, the posterior spinal artery, the posterior inferior cerebellar artery, the anterior inferior cerebellar artery, and the vertebral artery.

1.18.2 Pathways

The ascending tracts refer to the neural pathways by which sensory information from the peripheral nerves is transmitted to the cerebral cortex. In some texts, ascending tracts are also known as somatosensory pathways.

The descending tracts are the pathways by which motor signals are sent from the brain to the lower motor neurons. The lower motor neurons then directly innervate muscles to produce movement, discussed in Chapter 7.

1.19.1 Olfactory Nerve

This is the first and the shortest nerve. It is derived from the olfactory placode, a thickening of the neural ectoderm, which give rise to the olfactory epithelium of the nose containing the olfactory receptor neurons. These are bipolar cells that gives rise to unmyelinated axons, which are found in bundles and penetrate the cribriform plate of the ethmoid bone. They then enter the cranium and then the olfactory bulb to synapse with neurons called mitral cells, forming the synaptic glomeruli. From here, second-order neurons pass to the olfactory tract, which travels to the optic chiasm and divides into the two stria. The lateral stria carries axons to the primary olfactory cortex in the uncus of the temporal lobe and the medial stria to the anterior commissure, where they meet the olfactory bulb of the opposite side. The primary olfactory cortex sends fibers to the piriform cortex, the amygdala, the olfactory tubercle, and the secondary olfactory cortex.

The olfactory mucosa is found on the roof of the nasal cavity and is made up of pseudostratified columnar epithelium containing basal cells (which form new stem cells), sustentacular cells (for structural support, analogous to glial cells), olfactory receptor cells (bipolar cells consisting of dendrite processes with cilia that react to odors and stimulate olfactory cells), and a central process projecting in the opposite direction through the basement membrane. The mucosa also contains Bowman’s glands, which secrete mucus.

1.19.2 Optic Nerve

The optic nerve develops from the optic vesicle. It is a part of the central nervous system (CNS) and is covered by meninges. It is formed by the convergence of axons from the retinal ganglion cells, which in turn receive information from bipolar cells and the photoreceptors of the eye. Each optic nerve leaves its respective orbit via the optic canal, enters the middle cranial fossa, and unite to form the optic chiasm. Here, fibers from the nasal medial half of each retina cross to the contralateral optic tract; however, lateral fibers remain ipsilateral. Therefore, the right optic tract, for example, would contain fibers from the right temporal (lateral) retina but the left nasal retina. The optic tracts then reach the lateral geniculate nucleus (LGN) in the thalamus, which carries visual information in the optic radiation. The upper radiation carries fibers from the superior retinal quadrants (corresponding to the inferior visual field quadrants) through the parietal lobe to reach the visual cortex. The lower radiation carries fibers from the inferior retinal quadrants (corresponding to the superior visual field quadrants), through the temporal lobe, via Meyer’s loop, to reach the visual cortex for processing of visual information.

1.19.3 Oculomotor Nerve

The oculomotor nerve originates from the oculomotor nucleus at the level of the superior colliculus in the midbrain of the brainstem. It travels through the dura mater and enters the cavernous sinus. It leaves the cranium via the superior orbital fissure and divides into the superior branch to supply the superior rectus (which elevates the eyeball) and the levator palpabrae superioris (which raises the upper eyelid). It travels with sympathetic fibers that innervate the superior tarsal muscle (which helps to raise the eyelid). The inferior branch supplies the remaining extra ocular muscles (the inferior rectus depressing the eyeball, the medial rectus for adduction, and the inferior oblique for elevation, abduction, and lateral rotation). The Edinger–Westphal nucleus is dorsal to the oculomotor nuclei and contains preganglionic parasympathetic neurons to the ciliary ganglion. From here, postganglionic parasympathetic fibers supply the ciliary muscles for pupil constriction and the sphincter pupillae for accommodation.

Damage to the oculomotor nerves leads to ptosis, a down-and-out position of the eye and a dilated pupil. This can occur due to raised intracranial pressure, aneurysm of the posterior communicating artery, or damage to the cavernous sinus. It can also be found in other diseases such as multiple sclerosis and myasthenia gravis.

1.19.4 Trochlear Nerve

The trochlear nerve originates from the trochlear nuclei in the midbrain at the level of the inferior colliculus. It has the longest intracranial route because it is the only nerve to emerge from the dorsal brainstem, making it particularly vulnerable to damage. It travels within the cavernous sinus and passes through the superior orbital fissure to innervate the superior oblique muscle, which functions to depress, abduct, and intort the eye. Damage to this nerve leads to double vision and a characteristic head tilt toward the unaffected side.

1.19.5 Trigeminal Nerve

The trigeminal nerve provides sensory and motor innervation to the face. It originates from three sensory nuclei (the mesencephalic, principal sensory, and spinal nuclei) and one motor nucleus extending from the midbrain to the medulla. It has three branches, the ophthalmic, the maxillary, and the mandibular nerves, which arise from the trigeminal ganglion to provide sensory innervation to the face. The mandibular branch also supplies the muscles of mastication. Clinically, the corneal reflex can be performed to test damage to the ophthalmic nerve (which acts as the afferent limb to detect the stimulus) or the facial nerve (which is the efferent limb causing contract of the orbicularis oculi muscle).

1.19.6 Abducens Nerve

The abducens nerve is the sixth paired cranial nerve, with a somatic motor function to the lateral rectus muscle. It arises from the abducens nucleus in the pons, exiting the brainstem at the junction of the pons and the medulla. It then enters the subarachnoid space and pierces the dura mater, and enters the cavernous sinus through the superior orbital fissure. It can be damaged by any space-occupying lesion, which leads to diplopia and unopposed adduction.

1.19.7 The Facial Nerve

The facial nerve is derived from the second branchial arch. The upper motor neuron of the facial nerve is in the primary motor cortex, with its axons descending to the ventral and dorsal facial nucleus in the pons. The dorsal regions supply the muscles of the upper face and receive input from both hemispheres, and the ventral region supplies the muscles of the lower face and receives mainly contralateral inputs. The facial nerve passes through the internal auditory meatus and then on to the facial canal to synapse on the geniculate ganglion. It gives rise to the greater petrosal nerve, supplying the lacrimal gland, and joins the deep petrosal nerve to form the nerve of the pterygoid canal, innervating the pterygopalatine ganglion. It gives rise to the nerve to the stapedius muscle of the ear and the chorda tympani nerve, which supplies the submandibular ganglion and the anterior two thirds of the tongue.

The facial nerve leaves the cranium through the stylomastoid foramen and supplies the external ear, the external auditory meatus, the posterior belly of the digastric, the stylohyoid, the superior and inferior auricular, and the occipitalis muscles. It then travels to the parotid gland, and without supplying it splits into five branches (temporal, zygomatic, buccal, marginal mandibular, and cervical) to supply the muscles of facial expression.

1.19.8 Vestibulocochlear Nerve

The vestibulocochlear nerve has two main sensory divisions: the vestibular and cochlear nerves, which arise from the vestibular nuclei in the pons and medulla, and the cochlear nuclei in the inferior cerebellar peduncle, respectively. They combine at the pons and emerge at the cerebellopontine angle, exiting the cranium via the internal acoustic meatus. The vestibular nerve is responsible for equilibrium and the cochlear nerve is responsible for hearing.

The cochlea contains inner hair cells that respond to vibrations of sound and trigger action potentials from the spiral ganglia. Sound frequency is coded by the position of the activated inner hair cells.

The vestibular hair cells are found in the otoliths (the saccule and the utricule), where they detect linear motion of the head, and the semicircular canals (which detect rotational movement of the head), and coordinate balance. They are also important for the vestibulo-ocular reflex, which allows the stabilization of images on the retina while the head is moving.

Inflammation of the vestibular branch of the nerve can lead to vertigo, nystagmus, loss of equilibrium, and nausea/vomiting. Inflammation of the membranous labyrinth (labyrinthitis) can cause similar symptoms and in addition affect the cochlear nerve, leading to tinnitus.

1.19.9 Glossopharyngeal Nerve

The glossopharyngeal nerve begins in the medulla and leaves the cranium via the jugular foramen. It has mixed sensory and parasympathetic components. The sensory branch innervates the oropharynx via the pharyngeal branch, which merges with the vagus nerve to form the pharyngeal plexus. It forms the afferent limb of the gag reflex (the efferent limb is via the vagus nerve). It supplies the posterior one third of the tongue via the lingual branch and the palatine tonsils via the tonsillar plexus. It also supplies the carotid body and sinus. The tympanic branch of the nerve enters the middle ear and forms the tympanic plexus to supply the middle ear, tympanic membrane, and the eustachian tube. It supplies the stylopharyngeus muscle of the pharynx and provides parasympathetic innervation to the parotid gland.

1.19.10 Vagus Nerve

The vagus nerve extends from the medulla and exits the cranium, where it gives rise to an auricular branch and courses downward into the carotid sheath. At the base of the neck, the right vagus nerve enters the thorax anterior to the subclavian artery and the left vagus nerve passes between the left common carotid and subclavian arteries. In the neck it gives rise to pharyngeal branches (which supply the pharynx and soft palate), the external superior laryngeal nerve (which supplies the cricothyroid muscle), and the internal laryngeal branch (which supplies the laryngopharynx and part of the larynx). The right vagus nerve also gives rise to the recurrent laryngeal nerve (which supplies the intrinsic muscles of the larynx) and then forms the posterior vagal trunk in the thorax. The left vagus nerve forms the anterior vagal trunk. These contribute to the formation of the esophageal plexus innervating the smooth muscle of the esophagus. Cardiac branches to the heart arise in the thorax. The left vagus nerve gives rise to the left recurrent laryngeal nerve under the arch of aorta. The vagal trunks enter the abdomen via the esophageal hiatus in the diaphragm and then terminate into branches to supply the esophagus, the stomach, and the small and large intestines up to the splenic flexure.

1.19.11 Accessory Nerve

The accessory nerve has a somatic motor function and supplies the sternocleidomastoid and trapezius muscles. It contains spinal and cranial components. The spinal components arise from C1 to C6 spinal nerve roots, which merge and enter the cranium via the foramen magnum. After exiting the cranium, it descends to the sternocleidomastoid muscle and then to the posterior neck to supply the trapezius. The cranial component arises in the medulla and exits the cranium via the jugular foramen. It combines with the vagus nerve at the inferior ganglion.

1.19.12 Hypoglossal Nerve

The hypoglossal nerve supplies the extrinsic (genioglossus, hyoglossus, styloglossus) and intrinsic muscles of the tongue. The palatoglossus muscle is innervated by the vagus nerve. The hypoglossal nerve arises from the hypoglossal nucleus in the medulla and exits the cranium via the hypoglossal canal.

1.20.1 Functional Divisions

The cerebellum can be divided into three functional areas: the cerebrocerebellum, the spinocerebellum, and the vestibulocerebellum (Figure 1.28).

Figure 1.28

Functional divisions of the cerebellum.

The large division is the cerebrocerebellum, which is formed by the lateral hemispheres and is responsible for planning movements and motor learning. It also regulates muscle activation and visually guided movements. It receives inputs from the cerebral cortex and pontine nuclei. The fibers travel through the internal capsule and cerebral peduncles and terminate ipsilaterally in the pons and send their axons to the contralateral middle cerebellar peduncle. The cerebellum also receives information via the ascending spinocerebellar mossy fibers. Fibers from the inferior olive in the medulla form the climbing fibre input via the inferior cerebellar peduncle. They are thought to mediate plasticity in the mossy fiber–granule cell–Purkinje cell pathway to coordinate movement. Outputs from the dentate nucleus and the other deep cerebellar nuclei leave the superior cerebellar peduncle and then cross the midline at the lower midbrain, pass through the red nucleus and ascend to terminate in the thalamus. The cerebellum represents ipsilateral movement and sensation.

The spinocerebellum comprises the vermis and intermediate zone of the cerebellar hemispheres. It receives proprioceptive information and regulates body movements by allowing for error correction.

The vestibulocerebellum is the functional equivalent to the flocculonodular lobe. It controls balance and ocular reflexes, and receives inputs from the vestibular system and sends outputs back to the vestibular nuclei.

1.20.2 Deep Cerebellar Nuclei

The cortical output of the cerebellum, which is typically inhibitory, involves the deep cerebellar nuclei (Figures 1.28 and 1.29). There are three nuclei on each side: the dentate nucleus, the nucleus interpositus, and the fastigial nucleus. Some areas, such as the flocculus and the flocculonodular lobe, send outputs to the vestibular nuclei in the medulla. Together, the entire cerebellar output is transmitted to the brainstem descending motor pathways and the motor areas of the cerebral cortex via the thalamus.

Figure 1.29

Deep cerebellar nuclei.

1.20.3 The Cerebellar Peduncles

There are three peduncles that connect the cerebellum with the brainstem on each side. The middle peduncle is the largest and the superior peduncle is the major output pathway from the deep nuclei.

1.20.4 Cerebellar Cortex

The cerebellar cortex contains many tightly packed folds (folia). It has three well-defined layers: (i) an outer molecular layer consisting mainly of parallel fibers that run parallel to the folia and dendrites; (ii) the Purkinje cell layer containing large Purkinje cells; and (iii) a granule layer consisting of many small granule cells (Figure 1.30).

Figure 1.30

Layers of the cerebellum.

The Purkinje cells are the output cells of the cerebellar cortex. They have extensive dendrites and are intersected at right angles by the parallel fibers, allowing each Purkinje cell to receive and make synaptic contact with many parallel fibers along a single folium. The Purkinje cells send axons out of the cortex and inhibit cells in the deep cerebellar nuclei.

1.20.5 Vascular Supply

The cerebellum is supplied by the superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar arteries. The venous supply to the cerebellum includes the superior cerebellar veins draining to the straight sinus and internal cerebral veins and inferior cerebellar veins draining to the transverse sinus, superior petrosal sinus, and occipital sinus.

1.21.1 Neurovascular Supply

The arterial supply to the spinal cord is via the anterior spinal artery (a branch of the vertebral artery) and the two posterior spinal arteries (branches of the vertebral artery or the posteroinferior cerebellar artery), which anastomose in the pia mater. The segmental medullary arteries, of which the largest is the anterior segmental medullary artery (the artery of Adamkiewicz), also supply the spinal cord. Disruption of the blood supply to the spinal cord leads to nerve cell death and signs of weakness, paralysis, and loss of reflexes.

The spinal cord venous drainage includes an extrinsic and an intrinsic network. The extrinsic system includes radicular veins, the pial venous network, dorsal and ventral spinal veins. They are connected to the valveless vertebral venous plexuses, that communicate with the dural venous sinuses and are composed of an external plexus surrounding the vertebral column, internal plexus within the spinal canal (linked together via segmental veins) and basivertebral veins in the vertebral bodies. The intrinsic venous system includes the sulcal (drains to the anterior spinal veins) and radial veins (drains to the posterior spinal veins), linked by the transmedullary anastomotic veins within the parenchyma of the spinal cord.

The spinal nerves originate from the spinal cord and form the peripheral nervous system. They begin as anterior (motor) and posterior (sensory) nerve roots and unite at the intervertebral foramina to form a single spinal nerve, which leaves the vertebral canal via the intervertebral foramina and divides into the posterior and anterior rami (Figure 1.31).

Figure 1.31

Anatomical relations of a spinal nerve.

A peripheral nerve has an outer covering called the epineurium. Nerve fibers are organized into bundles called fascicles and each one is covered by the perineurium. Each individual neuron is covered by the endoneurium. Each individual neuron is covered by the endoneurium, a layer of delicate connective tissue around the myelin sheath of each myelinated nerve fiber in the peripheral nervous system (Figure 1.32).

Figure 1.32

Layers of a peripheral nerve.

A single spinal nerve innervates a strip of skin known as the dermatome and is used clinically to assess spinal injuries. During embryology the mesoderm adjacent to the neural tube (paraxial mesoderm) differentiates into 31 somites or segments. The ventral part gives rise to the ribs and vertebral column. The dorsal part consists of the dermomyotome. The dermatome forms the dermis, which eventually stretches to create a segmental innervation and the classic dermatome map (Figure 1.33).

Figure 1.33

The development of the dermatome.

1.21.2 Transverse Section of the Spinal Cord

The spinal cord contains inner gray matter surrounded by the white matter. The gray matter is divided into the dorsal horn, the intermediate column, the lateral horn, and the ventral horn. The dorsal horn contains neurons receiving somatosensory information. The ventral horn contains motor neurons that innervate skeletal muscle. The intermediate column and lateral horn contain neurons that innervate visceral and pelvic organs.

1.21.3 Rexed Laminae

The spinal cord can also be visualized in layers or laminae, where cells are grouped according to their structure and function (Figure 1.34). Lamina I contains cells that respond to noxious or thermal stimuli and sends information via the lateral spinothalamic tract. It corresponds to the marginal zone. Lamina II corresponds to the substance gelatinosa and is involved in sensation of all stimuli and moderates pain sensation. Lamina III is involved in proprioception and light touch sensation. Lamina IV is involved in non-noxious sensory information processing. Lamina V relays sensory information to the brain via the contralateral and spinothalamic tracts, and receives descending information from the brain via the corticospinal and rubrospinal tracts. Lamina VI receives proprioceptive information and sends information to the brain via ipsilateral spinocerebellar pathways and processes spinal reflexes. Lamina VII is a large region and receives information from lamina II to VI and relays motor information to the viscera. Lamina VIII is involved in modulating motor output to skeletal muscle. Lamina IX contains motor neurons innervating striated muscles and muscle spindles. Lamina X, known as the gray commissure, surrounds the central canal of the spinal cord and contains decussating axons.

Figure 1.34

Spinal cord laminae.

1.22.1 Neurulation (Formation of the Neural Tube)

The embryonic blastocyst develops into a two-layered structure: the epiblast and the hypoblast. In humans, the primitive streak, an opening on the epiblast midline forms ~14 days after fertilization. By the end of the third week, gastrulation occurs and the epiblast and hypoblast develop into the ectoderm and endoderm, respectively. The notochord is a rod of mesodermal cells that extends throughout the entire dorsal plane of the embryo and is responsible for inducing the overlying lateral edges of the ectoderm to form the neural plate (Figure 1.37), which will remodel to form a single closed tube. The notochord arises from a collection of cells called the Spemann–Mangold organizer. The discovery of these cells introduced the concept of induction in embryology where the identity of certain cells influences the development of surrounding cells. Later in development, the cranial and caudal portions of the neural tube form the brain and spinal cord, respectively. Closure of the neural tube is accompanied by accumulation of amniotic fluid in the central canal, which forms the primitive ventricular system the brain. The ventricular system is lined by the ventricular zone (VZ), which is an embryonic layer containing radial glial cells and is the site of neurogenesis during embryogenesis. The subventricular (SVZ) zone lies adjacent to this area, containing intermediate neuronal progenitor cells that divide into postmitotic neurons.

Figure 1.37

Formation of the neural plate.

1.31.1 Ocular Dominance

The neurons in the primary visual cortex of mammals contain monocular neurons in layer 4 and binocular neurons in the remaining layers. Neurons with the same eye preference are grouped together in ocular dominance (OD) columns. In the classic experiments by Reference TN and HubelHubel and Wiesel (1963), it was demonstrated that monocular deprivation of one eye in kittens during a critical period abolishes the ability of that eye to respond to visual stimulation and shifts the OD columns in favor of the open eye. However, a similar experiment in adult cats had no detrimental effect on vision. In humans, monocular deprivation from conditions such as strabismus can have the same effect, known as amblyopia, and can also lead to problems with depth perception.

1.31.2 Auditory Processing

Neurons in the primary auditory cortex (A1) are topographically arranged by their response to different frequencies. Organization of these tonotopic maps are genetically predetermined but refined in an activity dependent manner, through spontaneous activity and, following hearing onset. During critical periods, heightened plasticity drives maturation of specific features of the auditory system, such as identification of phonemes and language acquisition. However, this period is also exquisitely sensitive to impoverished environmental influences, which may have inadvertent effects on frequency tuning. Similarly, overexposure to pure tones may result in overrepresentation of the tone frequency within the map. Critical periods have also been described for other processes such as binaural hearing, which allows the localization of different sound sources. This can be greatly affected in childhood hearing loss associated with ear infections, with overrepresentation of stimuli to the unaffected ear and weakening of responses to the affected ear, resulting in reduced ability to navigate the auditory scene.

1.33.1 Rodents

There are several anatomical differences between human brains and those of rodents. Firstly, it is thought that humans have approximately 86 billion neurons compared to approximately 70 million in mice. The human brain cortex is folded, which increases its surface area, whereas the rodent cortex is smoother. Humans also have highly specialized regions for language and cognition. Rodents, however, have more evolved olfactory bulbs, necessary for their superior sense of smell.

Rats were historically the most popular animals used for neurobiological research due to their genetic and physiological similarities to humans. They are also larger in size than mice and therefore easier to handle and perform procedures on. However, the use of this model has declined largely due to the difficulties in directed manipulation of the rat genome.

Mice are formidable models for research in neuroscience. The ability to manipulate the mouse genome has allowed us to decipher the functions of genes and their role in disease processes. There are several advantages of using mice as models. They are small in size, allowing novel compounds to be delivered in smaller quantities for testing. They are also relatively cheap to maintain and reproduce quickly. They can also be inbred to yield identical strains, which removes genetic heterogeneity. The gene regulation networks are largely conserved in mice and human, however there are striking differences in gene expression patterns, and equally there are notable differences in immune responses, stress responses and metabolism between mice and humans. This often leads to disappointing results from clinical trials that are spurred on by positive results found in mouse studies. Rodent use in various physiological processes and diseases has been well described in the literature and the reader is directed to these sources for further reading.

1.33.2 Non-Human Primates

The use of non-human primates for basic neuroscience research has provided great insight into brain function and has allowed the testing of several therapeutic strategies used in human disease. Although there are many similarities between the human brain and the primate brain, there are notable anatomical differences. The human brain is 4.8 times bigger in size than it is for a comparable monkey (Figure 1.37). Human neocortex expansion has likely contributed to the higher cognitive abilities of humans. The prefrontal cortex forms a larger part of the human brain with a greater density of neurons compared to macaque brains. Other notable differences include a much smaller or absent fasciculus arcuatus (important for language processing) in non human primates. The consequence of an increase in size means that there is an increase in the number of specialized subregions such as the parietal cortex.

1.33.3 Drosophila

The use of Drosophila (fruit flies) has been instrumental in furthering advances in neuroscience, with many milestone discoveries made. The advantages and limitations of this model are shown in Table 1.1.

The Drosophila brain contains several discrete structures. These include the antennal lobes, important for the olfactory chemosensory pathway, and the mushroom bodies that are involved in olfactory associative learning and memory. A prominent structure in the central brain is the central body complex, which consists of four substructures: the fan-shaped body, the ellipsoid body, the paired nodule, and the protocerebral bridge. The central complex is involved in learning and memory, locomotor control, and courting behavior. The visual neuropils in the Drosophila form the optic lobe, which consists of four major substructures: the lamina, medulla, lobula, and the lobula plate. The subesophageal ganglion controls the mouth, salivary glands, and neck muscles (Figure 1.39).

Initial use of Drosophila for research was aimed at understanding the principles of heredity. Early studies of this model led to the discovery of balancer chromosomes, allowing the maintenance of mutations in essential genes without the need to genotype the animal for further breeding. Early demonstrations of how x-ray exposure can lead to genetic mutations, with resultant change in the genome, were conducted in Drosophila. The discovery of mitotic recombinations, where it was first demonstrated that reciprocal genetic exchange between chromosomes occurred outside the germlines, was first seen in Drosophila.

The importance of various genes in nervous system development, segmentation, and pattern formation were discovered using x-ray–induced mutations. The bithorax complex of genes and the polycomb gene were shown to be important in segmentation in the fruit flies.

Key genes involved in embryonic pattern formation and nervous system development such as Notch were first identified in Drosophila. The loss of Notch leads to the formation of an embryo with hypertrophied regions of the CNS and an underdeveloped ventral hypoderm, leading to premature differentiation into neuroblasts. Components of its pathway such as neuralized are also important in learning and memory.

Larval Drosophila were among the first species to be used as a model for synaptic transmission through the study of their neuromuscular junction (NMJ). Presynaptic and postsynaptic genetic manipulation techniques were used to discover the functions of many proteins, including the roles of synaptotagmin as a calcium sensor.

1.33.4 Zebrafish

The zebrafish has become an instrumental model in answering fundamental questions about the brain and has recently seen many sophisticated applications in investigating clinical diseases. The zebrafish contains many structures that are similar to other vertebrates. Approximately 6 hours post fertilization (hpf), the CNS begins to develop. By 24 hpf, the brain can be distinguished into the forebrain, midbrain, and hindbrain (Figure 1.40). The forebrain further differentiates into the telencephalon, the diencephalon, the hypothalamus, and the retina.

Figure 1.40

Zebrafish developmental timeline.

The telencephalon in zebrafish is composed of the subpallium (ventral telencephalon), the pallium (dorsal telencephalon), and the olfactory bulb. The subpallium in the zebrafish serves a similar function as the mammalian basal ganglia. The ventral telencephalon contains the ventral nucleus and a dorsal nucleus. GABAergic and cholinergic neurons are formed in this region. The dorsal telencephalon is composed of a more complex array of regions including the central, lateral, posterior, and dorsomedial zones. It serves a similar function to that of the hippocampus and amygdala in mammals. The olfactory bulb of the telencephalon receives odor information.

The zebrafish diencephalon is composed of the thalamus, pineal body, and habenula. The habenula connects the forebrain with the midbrain and hindbrain, and is involved in fear modulation, reproductive behavior, and sleep initiation.

The hindbrain is easily visualized in the zebrafish. Numerous motor neurons and those that innervate the branchial arches and the cerebellum originate here. The hindbrain contains reticulospinal neurons including the Mauthner cell, which mediates escape responses.

The zebrafish has several advantages as an animal model, including small size and low maintenance costs. Zebrafish larvae have further advantages in being easily manipulated, permeable to small molecules, rapidly generated, optically translucent, and having non-protected status prior to 5 days post fertilization (dpf). The zebrafish genes are thought to share approximately 70% homology with that of human genes and has high homology to mammalian biology. The zebrafish possesses conserved neural circuits underlying basic behaviors and pathways and is therefore likely to be relevant for translational research. Neurons are accessible during in vivo imaging and can therefore be used to investigate how neuronal circuits are involved in complex behavior.

The behavioral repertoire of zebrafish larvae has been exploited to not only understand the functions of distinct regions of the brain but also to test various neuropharmacologic agents. Zebrafish have a developmentally regulated BBB, which is functional at 10 dpf and is therefore ideal for testing drugs. Behavior that is commonly tested in zebrafish includes thigmotaxis (the tendency to move toward the periphery of an environment) for testing anxiety, startle responses to various stimuli, and optomotor responses, an innate visuomotor reflex, initiated by neurons in the pretectum/tectum or through the activation of hindbrain integrator neurons which activate downstream motor commands. Locomotion play an integral role in the feeding, social, and defensive activities of the zebrafish and is produced by reticulospinal neurons of the brainstem along with descending vestibulospinal or neuromodulatory projections. The sleep/wake pattern of the zebrafish is similar to humans and provides great insight into the biology of the circadian rhythms and can be used as a model to study human sleep. Other behavior paradigm tests include habituation (to test non associative learning) and prey capture (decision making and cognition).

The zebrafish has also been used to model various clinical diseases. These include neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. It has also been used to model brain tumors (Figure 1.41), intracerebral hemorrhage, and arteriovenous malformations.

Figure 1.41

Zebrafish larvae at 5dpf showing glioblastoma tumor growth (green)

The use of zebrafish for translational research is still at an infantile stage for many diseases and therefore requires rigorous testing and exploration. For example, although it is exceptional for large scale pharmacologic testing, the route of administration of drugs in zebrafish includes passive exposure in water rather than active administration and therefore may produce differing results in humans.

1.33.5 Caenorhabditis elegans

Caenorhabditis elegans is a nematode approximately 1 mm in size. It is a formidable organism for the study of genomes that may otherwise be difficult in mammalian systems. As an animal model it has several advantages, such as a transparent body, a short life cycle, and fecundity. Furthermore, as they are self-fertilizing hermaphrodites, each progeny represents a genetic clone.

The C. elegans lineage is invariant and the complete cell lineage for the 959 cells in the adult has been described. The sequencing of the genome has also demonstrated that approximately 38% of worm genes have a human ortholog and therefore provides opportunity for it to be used as an in vivo model for the study of certain human conditions. It also has a compact genome size and therefore genetic screens can be conducted to further elucidate the molecular underpinnings of certain behaviors.

The complete connectome of C. elegans contains 302 neurons for the adult hermaphrodite. It has been used to further our understanding of well-known signaling pathways and study the complexities of the nervous system.

It has been particularly useful for studying memory and learning. These organisms have an ability to quickly make decisions, and this is observed when presented with harmful substances; however, when this is simultaneously presented with attractive odorants, it decides whether to migrate to the attractive odorant or avoid it due to its proximity to the harmful substance. It also possesses long-term memory as evidenced by its enhanced attractive responses to certain odors as adults if it was previously exposed to this at the larval stage.

1.33.6 Hydra

Hydra was discovered at the beginning of the eighteenth century. Since then, it has been used as an animal model to improve our understanding of fundamental processes in animal biology (Figure 1.42). In 1744, Trembley published his Mémoires, which provided the first description of asexual reproduction by budding, the first controlled experiments in animals on regeneration, the first successful animal grafts, the first study of phototaxis in animals without eyes, and the first vital staining of tissues. Later, Ethel Browne Harvey used Hydra in a series of experiments that introduced a new concept in developmental biology, known as the organizer phenomenon. More specifically, she showed that when grafting the tentacle of one Hydra onto the body column of another Hydra, one can trigger the growth of a new Hydra at the grafting site. This new Hydra would develop normally as if it had been the result of budding or asexual reproduction.

Figure 1.42

Gross structure of the Hydra.

Hydra has been studied for more than 300 years, mostly because of how easy it is to culture and manipulate in a laboratory. Hydra can grow and shrink by an order of magnitude (from 1 mm to 1 cm) depending on various factors such as food availability and environmental temperature. Consequently, its nervous system is composed of a variable number of neurons from a few hundred to a few thousand depending on the size of the animal. Traditionally, two main types of neurons have been reported: sensory cells, exposed to the external or gastric environment, and ganglion cells, which form a two-dimensional lattice known as a nerve net. Moreover, the nerve net of Hydra is made up of two separate components: the endodermal nerve net and the ectodermal nerve net. The morphology of both sensory cells and ganglion cells can vary in terms of the size of their cell body and the ramification of their neurites.

The behavioral repertoire of Hydra is quite limited and includes basic behaviors such as periodic contractions of the body column on the longitudinal axis and along its radius, photic response, and feeding.

Establishing links between neuronal activity, anatomy, and behavior in Hydra has been challenging because of technical limitations. When it comes to electrophysiology, single-cell recording approaches such as sharp electrode recordings are not possible because Hydra neurons are small and spread out. On the other hand, with extracellular recordings (e.g., using suction electrodes) it is difficult to precisely localize their source. For these reasons it has not been possible until recently to measure how many networks exist in the nervous system of Hydra and in what behavior each of them participates.

The application of modern methods in molecular biology to Hydra has the potential to greatly advance our understanding of its nerve net. The sequencing of the Hydra genome makes it possible to study its surprisingly rich repertoire. Indeed, despite its basal metazoan lineage, the Hydra genome comprises more than 20,000 genes including a large number of neuronal genes such as sodium, potassium, and calcium channels, and receptors for glutamate, GABA, dopamine, serotonin and a vast array of neuropeptides. Also, methods for creating stable transgenic lines have been developed, enabling the use of a large range of modern molecular tools. Among these tools, genetically encoded calcium indicators are particularly well suited to study the activity of the nervous system of Hydra for multiple reasons as they are small, transparent, and contain neurons that are widely scattered.