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In the present paper, we have further developed an in vitro model to study neuronal–glial interaction at trigeminal level by characterizing the effects of conditioned medium (CM) collected from activated primary cultures of satellite glial cells (SGCs) on calcitonin gene-related peptide (CGRP) release from rat trigeminal neurons. Moreover, we investigated whether such release is inhibited by a clinically relevant anti-migraine drug, sumatriptan. CM effects were tested on trigeminal neuronal cultures in different conditions of activation and at different time points. Long-term exposures of trigeminal neurons to CM increased directly neuronal CGRP release, which was further enhanced by the exposure to capsaicin. In this framework, the anti-migraine drug sumatriptan was able to inhibit the evoked CGRP release from naïve trigeminal neuron cultures, as well as from trigeminal cultures pre-exposed for 30 min to CM. On the contrary, sumatriptan failed to inhibit evoked CGRP release from trigeminal neurons after prolonged (4 and 8 h) pre-exposures to CM. These findings were confirmed in co-culture experiments (neurons and SGCs), where activation of SGCs or a bradykinin priming were used. Our data demonstrate that SGCs activation could influence neuronal excitability, and that this event affects the neuronal responses to triptans.
Vinpocetine has long been used for cerebrovascular disorders and cognitive impairment. Based on the evidence that the translocator protein (TSPO, 18 kDa) was expressed in activated microglia, while Vinpocetine was able to bind TSPO, we explored the role of Vinpocetine on microglia treated with lipopolysaccharide (LPS) and oxygen–glucose deprivation (OGD) in vitro. Our results show that both LPS and OGD induced the up-regulation of TSPO expression on BV-2 microglia by RT-PCR, western blot and immunocytochemistry. Vinpocetine inhibited the production of nitrite oxide and inflammatory factors such as interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α (TNF-α) in BV-2 microglia, in which cells were treated with LPS or exposed to OGD, regardless of the time Vinpocetine was added. Next, we measured cell death-related molecules Akt, Junk and p38 as well as inflammation-related molecules nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Vinpocetine did not change cell death-related molecules, but inhibited the expression of NF-κB and AP-1 in LPS-stimulated microglia, indicating that Vinpocetine has an anti-inflammatory effect by partly targeting NF-κB/AP-1. Next, conditioned medium from Vinpocetine-treated microglia protected from primary neurons. As compared with in vitro, the administration of Vinpocetine in hypoxic mice also inhibited inflammatory molecules, indicating that Vinpocetine as a unique anti-inflammatory agent may be beneficial for the treatment of neuroinflammatory diseases.
Glutathione S-transferases (GSTs) are major intracellular antioxidants, which, impaired in their function, are involved in the progress of schizophrenia (SCZ). The aim of this case-control study was to investigate the association between the polymorphism of glutathione S-transferases M1 (GSTM1), T1 (GSTT1), the glutathione S-transferase P1 gene (GSTP1) and SCZ. We isolated genomic DNA from peripheral blood of 93 individuals with SCZ and 99 healthy control subjects' genotypes analyzing them for GSTM1, GSTT1 and GSTP1 using polymerase chain reaction. The analysis of the gene–gene interaction between GSTs indicated that the magnitude of the association was greater for the combined AG/GSTT1 & GSTM1 genotypes (OR = 2.51; 95% CI: 1.13–5.63, P = 0.02). The AG and combined AG + GG genotypes of GSTP1 increased the risk of SCZ (OR = 1.83; 95% CI: 0.94–3.75 and OR = 1.71; 95% CI: 0.92–3.19, respectively). The genotypes of GSTT/NULL, NULL/GSTM and NULL/NULL increased the risk of SCZ (OR = 2.05; 95% CI: 0.9–4.74; OR = 2.0; 95% CI: 1.68–2.31; and OR = 1.8; 95% CI: 0.57–2.46, respectively). The present study supports previous data that suggest that impairment in the function of GSTs genes may increase the risk of SCZ.
Previously studied for its role in processing olfactory information in the antennal lobe, GABA also may shape development of the olfactory pathway, acting either through or on glial cells. Early in development, the dendrites of GABAergic neurons extend to the glial border that surrounds the nascent olfactory lobe neuropil. These neuropil glia express both GABAA and GABAB receptors, about half of the glia in acute cultures responded to GABA with small outward currents, and about a third responded with small transient increases in intracellular calcium. The neuronal classes that express GABA in vivo, the local interneurons and a subset of projection neurons, also do so in culture. Exposure to GABA in culture increased the size and complexity of local interneurons, but had no effect on glial morphology. The presence of glia alone did not affect neuronal morphology, but in the presence of both glia and GABA, the growth-enhancing effects of GABA on cultured antennal lobe neurons were eliminated. Contact between the glial cells and the neurons was not necessary. Operating in vivo, these antagonistic effects, one direct and one glia mediated, could help to sculpt the densely branched, tufted arbors that are characteristic of neurons innervating olfactory glomeruli.
Evidence indicates that children with autism spectrum disorder (ASD) suffer from an ongoing neuroinflammatory process in different regions of the brain involving microglial activation. When microglia remain activated for an extended period, the production of mediators is sustained longer than usual and this increase in mediators contributes to loss of synaptic connections and neuronal cell death. Microglial activation can then result in a loss of connections or underconnectivity. Underconnectivity is reported in many studies in autism. One way to control neuroinflammation is to reduce or inhibit microglial activation. It is plausible that by reducing brain inflammation and microglial activation, the neurodestructive effects of chronic inflammation could be reduced and allow for improved developmental outcomes. Future studies that examine treatments that may reduce microglial activation and neuroinflammation, and ultimately help to mitigate symptoms in ASD, are warranted.
Modulation of astroglial components involved in reactive postlesional responses in the rat cerebral cortex was analyzed following exposure to environmental enrichment (EE) condition prior to injury. For this purpose, changes in % immunoreactive (IR) area of GFAP, vimentin, EAAT1 and ezrin were evaluated in the perilesional zone after placing a cortical stab wound in the visual cerebral cortex of adult rats. GFAP-IR postlesional reactive astrocytosis in the perilesional cortex was significantly lower in the animal group exposed to EE during postnatal development. This GFAP-IR reaction seems to be associated with existing astroglia, because neither BrdU- nor endogenous Ki-67-labeled nuclei were found in the perilesional cortex analyzed. Increased ezrin-IR area in the visual cortex of rats exposed to EE condition suggests the formation of new synapses or the enhancement of astroglial involvement in the existing ones. No effects of EE were found on either EAAT1- or vimentin-IR area. Results suggest that exposure to EE conditions prior to injury attenuates the postlesional astroglia GFAP-response in the perilesional cortex of rats. Whether this attenuated postlesional astroglia GFAP-response promotes or not protective effects on the cortical neuropil remains to be explored in futures studies.
Memory consolidation in a discriminative bead pecking task is modulated by endogenous adenosine triphosphate (ATP) acting at purinergic receptors in the hippocampus. Consolidation, from short- to intermediate- to long-term memory during two distinct periods following training, was blocked by the non-selective P2 purinergic receptor antagonist PPADS (pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) tetrasodium salt hydrate and the specific P2Y1 receptor antagonist MRS2179. Direct injections of the ATP agonists (ATPγS and ADPβS) potentiated memory consolidation and the effect of ADPβS was blocked by MRS2179, suggesting an important role of ATP on memory consolidation via the P2Y1 receptor in the chick hippocampus. Incubation of astrocytes with ATPγS and ADPβS resulted in the increase of intracellular calcium ([Ca2+]i), the latter being blocked by MRS2179 suggesting a specific role for P2Y1 receptors in the calcium response. This response was prevented by blocking astrocytic oxidative metabolism with fluoroacetate. We argue that the source of the ATP acting on neuronal P2Y1 receptors is most likely to be astrocytes. Thrombin selectively increases [Ca2+]i in astrocytes but not in neurones. The main findings of the present study are: (a) astrocytic [Ca2+]i plays an important role in the consolidation of short-term to long-term memory; and (b) ATP released from chick astrocytes during learning modulates neuronal activity through astrocytic P2Y1 receptors.
Recently, an interest in our understanding of well-being within the context of competition and cooperation has re-emerged within the biological and neural sciences. Given that we are social animals, our well-being is tightly linked to interactions with others. Pro-social behavior establishes and sustains human contact, contributing to well-being. Adaptation and Well-Being is about the evolution and biological importance of social contact. Social sensibility is an essential feature of our central nervous systems, and what have evolved are elaborate behavioral ways in which to sustain and maintain the physiological and endocrine systems that underlie behavioral adaptations. Writing for his fellow academics, and with chapters on evolutionary aspects, chemical messengers and social neuroendocrinology among others, Jay Schulkin explores this fascinating field of behavioral neuroscience.
One feature that underlies cephalic regulation of behavior is the diverse social cues for approach and avoidance. The greater the sophisticated social context, the larger the cognitive/behavioral strategies to draw upon (Byrne and Bates, 2007). Behavioral approach and avoidance are both cognitively and affectively driven; all neural systems are rich in information processing, and therefore cephalic adaptation of all sorts is cognitive in nature. The issue is not really cognitive versus not cognitive, but how flexible, labile and adaptive the systems are (Gallistel, 1980).
In this chapter, I underscore the diverse information molecules that underlie adapting change or allostasis. Many of them reflect feedforward systems: steroids facilitating neuropeptide expression, adapting and coping with social change or social stability (Herbert and Schulkin, 2002). The chapter begins with a theme broached in the last chapter with regard to organization and structural changes in the brain that underlie diverse forms of social behavior, followed by a discussion of appetitive and consummatory motivated behaviors essential for successful social behavioral adaptations. I begin first with a discussion of appetitive and consummatory concepts, followed by describing socially related phenomenon.
APPETITIVE AND CONSUMMATORY BEHAVIORS
Just what are they? An early description by Craig (1918) depicted diverse appetitive approach behaviors, and consummatory behaviors in diverse species; central states of the brain underlie the search engine and the consummatory phase of motivation (Stellar, 1954). The motivation for rewards pervades ecological space.
As Aristotle noted long ago, we are, by nature, social animals. Human evolution has increased the importance of social knowledge and social context. Prosocial behavior underlies the moral sensibility that pervades human experience resulting in significant human contact.
Darwin emphasized a fundamental prosocial feature of us, essential for moral judgment. He asserted, “… any animal whatever, endowed with a well-marked social instinct, the parental and filial affections being here included would inevitably acquire a moral sense of conscience, as soon as its intellectual power had become as well or nearly as well developed as in man” (1874: 95). However, in Descent of Man, Darwin also noted the “the fewness and the comparative simplicity of the instincts in the higher animals are remarkable in contrast with those of the lower animals” (1874: 65).
Adapting to the social milieu is a fundamental feature of our species. Darwin, like others before and since, understood that we are social animals. What has emerged in Homo sapiens has been an elaboration of social contact, the expansion of individual responsibility manifested in specific types of the division of labor in the service of group safety and human well-being and productivity. There has also been a technical expansion resulting in the development of a diverse supply of cognitive resources, including cognitive resources which pitted, at times, deception against social cooperation as conflicting motivations (Dunbar and Shultz, 2007).
We have come to realize, as a normative goal, that social hope is our common bond – the dilution of differences that divide and harm us. The path of human progress is frail; with glimmers of hope, the eternal seduction, the stoic nobility exists amidst the diffidence and difficulties in preserving a broad social compass in which many reach forms of meaningful human happiness rich in existential sensibility.
However, there is no panacea; the idea of progress that infused Darwin's conception of evolution and Jackson's and Spencer's conception of the nervous system has been modified. Corticalization of function does not necessarily mean social advance. Devolution of function is as paramount as times of war and crisis.
Prosocial sensibilities figure importantly and are a constant across cultures, but they compete with diverse motivations. Variation in expression is a constant, but social contact is also a factor across all cultures, and the formation of habits sets the conditions for meaningful lasting social contact (Jaspers, 1913/1997).
EVOLUTION AND ADAPTATION
At one fundamental level, little has changed: we search for the stable amidst the precarious (Dewey, 1925/1989). The search requires diverse cephalic and cultural resources, and results in punctuated and gradual cultural epicenters. The human condition remains more precarious, our weapons that much more dangerous, and the level of potential destruction that much greater. The precarious shifts towards the more stable by cephalic adaptation.
We live in a social world with exorbitant and ever-present rewards: from chocolates to stocks, from achievement to thermal comfort. The search for reward is a constant occupation. It is not very surprising that for centuries the concept of reward and human occupation have gone hand in hand in defining our existence, and of course, more than one species is characterized by the search for satisfaction and the avoidance of what is not pleasing.
Diverse theories about pleasure-seeking and pain-avoidance have dominated our intellectual landscape. Hedonism, in both its ancient and modern forms, describes the endless human search for what feels good and the avoidance of what does not. In the broadest sense, hedonic theories are not wrong when construed in terms of the search for satisfaction; but narrowly construed, on the model of a piece of chocolate, the theory does not characterize the full range of our behavioral dispositions, nor that of other species.
Abstract atoms of sensation cauterized from classical hedonism through David Hume (1984/1739) have never done full conceptual justice to the concept of objects. It is objects that orient us, not simple sensation. We are rooted in a world of objects. It is the sight of the bear that renders us afraid, setting off the transduction mechanisms in a well-designed cephalic system to detect and avoid danger. We are oriented towards the object of fear, not its sensation. That is not to deny sensation, for surely that would be a false claim.
A key feature in evolution is how well the behavioral/physiological adaptation works, and how flexible the particular adaptation can be when expanded into diverse contexts. Our evolution reveals a conception, not always accurate, that rigidity is a feature of lower species, whereas flexibility is a feature of primates such as us. Corticalization of function reflects the larger role that social, cognitive and anticipatory regulation of the social and internal milieu play in the organization of behavioral and physiological viability (James, 1890/1952).
Responding to diverse social signals requires a flexible brain with a range of behavioral options. Our evolution is linked to our cognitive competence and one feature of this is our social contact, both cooperative and competitive. Competition often requires cooperative understanding to ensure success, depending upon one's view of evolution and the cultural context in which cooperation and competition are understood. Evolution has selected both and one should be wary about mythologizing one or the other in our conceptual framework. This chapter orients the reader towards several conceptions of evolution and their importance in understanding our cephalic expansion, which underlies our diverse forms of behavioral and physiological adaptations to changing contexts.
EXPLANATIONS IN THE CONTEXT OF EVOLUTION
The great taxonomists, starting from Aristotle, have created long catalogues of natural objects and, in this case, the lineages relating biological taxa and species. Recognition of kinds of objects is a predilection that comes with our cognitive endowment; we are taxonomic animals. Evolution favored this cognitive ability in our species.
As Darwin (1859/1958) noted, social instincts are the prelude for much of what governs our social evolution; climatic variation and stability perhaps fostered group formation as an important evolutionary adaptation – linking up with others, helping them, being helped. Of course the debate over the extent to which our behavior is governed by instincts has had a long and torturous history (James, 1890/1952). The social instincts are used to get linked to others and are bound to the development of a variety of social cognitive skills used to deceive (Mithen, 1996), trust, and engage in both social contact and social withdrawal. However, these instincts lie mostly in the formation of important alliances that underlie our cognitive evolution, amidst language and a set of diverse cognitive adaptations that root us in the world, a world in which epistemological and practical action predominate.
Both cultural and physiological/ecological stability are important factors in our evolution as are the diverse forms of adaptations that underlie coping with periods of non-stability. The search for stability and coherence amidst social insecurity is a fundamental feature that underlies human motivation and social investigation. In this chapter, I begin with an orientation of neuronal structure and function; a changing sense of our understanding of the organization of action through envisioning both the motor regions and limbic regions (e.g. information molecules that changed our conception of the classical limbic system) is vital for the expanding cognitive adaptations that figure in our social attachments and the allocation of cognitive resources for sustaining viable responses to changing landscapes.
Diverse regions of the brain are essential for action and are often activated earlier than the action themselves; regions of the brain such as the basal ganglia (Swanson, 2000) are bound to diverse forms of cognitive actions, including prosocial ones. Diverse information molecules underlie prosocial behaviors (e.g. oxytocin, vasopressin, and serotonin).
A developmental perspective has emerged positing that neonates are rooted in the world of objects and transactions with others from birth (Kagan, 1984). Their aim is towards getting coherence in a social world; social cognitive dispositions predominate amongst other cognitive/physiological predilections essential for adaptation and coherence of action. Making sense of others is thus a core adaptation. So we come prepared to make sense of the objects around us – particularly con-specifics.
In this chapter, I discuss again corticalization of function, from a received view, not incorrect but perhaps overstated – namely that the cortex restrains the more primitive brain (e.g. amygdala). In addition, in this chapter, the role of diverse information molecules (oxytocin, CRH, dopamine, serotonin) in social approach and avoidance behaviors continues to be discussed, amidst a further understanding of both neocortical sites and amygdala function in the organization of action.
CONSIDERATIONS ABOUT THE NEOCORTEX
For over a century, we have known that cortical function is bound to more elaborate cognitive capacities; in fact, the nineteenth century was dominated by this realization. From a comparative perspective, the frontal cortex, for instance, makes transparent an expansion of the primate brain.
Evolutionary factors leave their imprint across all life processes; one core event is the organization of the brain. Brains vary with species, with taxa; linking a conception of evolution with brain function required a conception of the nervous system, its core outline, variation and common themes (Swanson, 2000).
The nineteenth-century British neurologist J. Hughlings Jackson formulated a conception of the nervous system that places the brain within evolution; the brain is understood in terms of levels of function. The neocortex represented a crowning achievement, increasing the range of action.
This was, of course, understood for some time; Jackson's conception of the nervous system in the nineteenth century had cortical tissue, the evolutionary mantle of the brain, underlying the selection of options, in which brainstem sites carried out the basic functions. Devolution of function, typically for Jackson, was linked to forebrain damage, thereby limiting capacity and reducing behavioral options; what evolved was the range of opportunities that reflects the corticalization of function.
Of course, the mantle of progress with corticalization of function was at the center of an egocentric human conception of evolution, with social bonds, social history, human invention, rational decision forming being the pillars of social ascent. The march of progress was the conception, both in terms of biological and cultural evolution.