It has taken more than 40 years for the fields of immunology and neuroscience to capture the potential impact of the mechanistic understanding of how an active immune signalling brain might function. These developments have grown an appreciation for the immunocompetent cells of the central nervous system and their key role in the health and disease of the brain and spinal cord. Moreover, the understanding of the bidirectional communication between the brain and the peripheral immune system has evolved to capture an understanding of how mood can alter immune function and vice versa. These concepts are rapidly evolving the field of psychiatry and medicine as a whole. However, the advances in human medicine have not been capitalised upon yet in animal husbandry practice. Of specific attention are the implications that these biological systems have for creating and maintaining heightened pain states. This review will outline the key concepts of brain–immune communication and the immediate opportunities targeting this biology can have for husbandry practices, with a specific focus on pain.

Animal models are valuable for the study of complex behaviours and physiology such as the control of appetite because genetic, pharmacological and surgical approaches allow the investigation of underlying mechanisms. However, the majority of such studies are carried out in just two species, laboratory mice and rats. These conventional laboratory species have been intensely selected for high growth rate and fecundity, and have a high metabolic rate and short lifespan. These aspects limit their translational relevance for human appetite control. This review will consider the value of studies carried out in a seasonal species, the Siberian hamster, which shows natural photoperiod-regulated annual cycles in appetite, growth and fattening. Such studies reveal that this long-term control is not simply an adjustment of the known hypothalamic neuronal systems that control hunger and satiety in the short term. Long-term cyclicity is probably driven by hypothalamic tanycytes, glial cells that line the ventricular walls of the hypothalamus. These unique cells sense nutrients and metabolic hormones, integrate seasonal signals and effect plasticity of surrounding neural circuits through their function as a stem cell niche in the adult. Studies of glial cell function in the hypothalamus offer new potential for identifying central targets for appetite and body weight control amenable to dietary or pharmacological manipulation.

The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.

The regional heterogeneity of neuronal phenotypes is a well-known phenomenon. Whether or not glia derived from different brain regions are phenotypically and functionally distinct is less clear. Here, we show that microglia, the resident immune cells of the brain, display region-specific responses for activating agents including glutamate (GLU), lipopolysaccharide (LPS) and adenosine 5′-triphosphate (ATP). Primary microglial cultures were prepared from brainstem (Brs), cortex (Ctx), hippocampus (Hip), striatum (Str) and thalamus (Thl) of 1-day-old rats and were shown to upregulate the release of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) in a region- and activator-specific manner. With respect to ATP specifically, ATP-induced changes in microglial tumor necrosis factor-α (TNF-α) release, GLU uptake and purinergic receptor expression were also regionally different. When co-cultured with hypoxia (Hyp)-injured neurons, ATP-stimulated microglia from different regions induced different levels of neurotoxicity. These region-specific responses could be altered by pre-conditioning the microglia in a different neurochemical milieu, with taurine (TAU) being one of the key molecules involved. Together, our results demonstrate that microglia display a regional heterogeneity when activated, and this heterogeneity likely arises from differences in the environment surrounding the microglia. These findings present an additional mechanism that may help to explain the regional selectiveness of various brain pathologies.

There is a growing body of evidence suggesting a functional relationship between Ca2+ signals generated in astroglia and the functioning of nearby excitatory synapses. Interference with endogenous Ca2+ homeostasis inside individual astrocytes has been shown to affect synaptic transmission and its use-dependent changes. However, establishing the causal link between source-specific, physiologically relevant intracellular Ca2+ signals, the astrocytic release machinery and the consequent effects on synaptic transmission has proved difficult. Improved methods of Ca2+ monitoring in situ will be essential for resolving the ambiguity in understanding the underlying Ca2+ signalling cascades.

Astrocytes are involved in synaptic and cerebrovascular regulation in the brain. These functions are regulated by intracellular calcium signalling that is thought to reflect a form of astrocyte excitability. In a recent study, we reported modification of the genetically encoded calcium indicator (GECI) GCaMP2 with a membrane-tethering domain, Lck, to generate Lck-GCaMP2. This GECI allowed us to detect novel microdomain calcium signals. The microdomains were random and ‘spotty’ in nature. In order to detect such signals more reliably, in the present study we further modified Lck-GCaMP2 to carry three mutations in the GCaMP2 moiety (M153K, T203V within EGFP and N60D in the CaM domain) to generate Lck-GCaMP3. We directly compared Lck-GCaMP2 and Lck-GCaMP3 by assessing their ability to monitor several types of astrocyte calcium signals with a focus on spotty microdomains. Our data show that Lck-GCaMP3 is between two- and four-times better than Lck-GCaMP2 in terms of its basal fluorescence intensity, signal-to-noise and its ability to detect microdomains. The use of Lck-GCaMP3 thus represents a significantly improved way to monitor astrocyte calcium signals, including microdomains, and will facilitate detailed exploration of their molecular mechanisms and physiological roles.

An important protective function of the brain's innate immune system is to detect the presence of proteins such as amyloid and to remove them before they become neurotoxic, as is thought to occur in Alzheimer's disease (AD). Ageing affects the immune system response to infection and can influence the systemic response to vaccination and other potential immunotherapeutic agents. The generation of systemic antibodies is a vital component of the immune response, facilitating the identification and clearance of pathogens from the central nervous system (CNS). Experimental evidence using transgenic animal models of AD has shown successful clearance of amyloid from the CNS following vaccination with an amyloid peptide, and consequently a trial of amyloid beta peptide (Aβ) vaccination was undertaken in older people with AD. This produced some unexpected results, as not only was there evidence for amyloid plaque removal, but also a small number of cases developed encephalitis. A detailed review of the response to vaccination and the neuropathology findings are discussed, showing that the findings are understandable given the effects of ageing upon the innate immune system in the brain. Finally, the therapeutic potential of manipulating the regulatory components of the ageing innate immune system in order to inhibit brain inflammation and reduce cognitive decline is outlined.

Intercellular coupling by gap junctions is one of the main features of glial cells, but very little is known about this aspect of satellite glial cells (SGCs) in sympathetic ganglia. We used the dye coupling method to address this question in both a prevertebral ganglion (superior mesenteric) and a paravertebral ganglion (superior cervical) of mice. We found that in control ganglia, the incidence of dye coupling among SGCs that form the envelope around a given neuron was 10–20%, and coupling between SGCs around different envelopes was rare (1.5–3%). The dye injections also provided novel information on the structure of SGCs. Following peripheral inflammation, both types of coupling were increased, but most striking was the augmentation of coupling between SGCs forming envelopes around different neurons, which rose by 8–14.6-fold. This effect appeared to be non-systemic, and was blocked by the gap junction blocker carbenoxolone. These changes in SGCs may affect signal transmission and processing in sympathetic ganglia.

We have used light- and electron-microscopic immunohistochemistry to identify the presence of immunoreactivity to neuropeptide Y (NPY) within Müller cells in the retina of the cane toad, Bufo marinus. Müller cells containing NPY-like immunoreactivity (NPY-LI) were identified at the light-microscopic level by the coexistence with immunoreactivity to glial fibrillary acidic protein (GFAP) and at the ultrastructural level by their characteristic relationship to neuron cell bodies and processes. At the light-microscopic level, those cells which contained both NPY-LI and GFAP-LI usually had small cell bodies in the inner nuclear layer, while those cells which contained only NPY-LI were identified as large and small amacrine cells. The radially oriented primary processes in the inner plexiform layer and the vitreal end feet of GFAP-LI Müller cells also expressed NPY-LI. At the ultrastructural level, thin lamellar processes of Müller cells with NPY-LI enclosed some amacrine cell bodies in the inner nuclear layer and amacrine cell dendrites in the inner plexiform layer. These observations suggest that NPY-LI is localized in Müller cells in addition to two types of amacrine cells previously identified in the Bufo retina. This study provides the first evidence that glial elements in the vertebrate retina express NPY-LI.

Although it is well known that neurotransmitters mediate neuron-to-neuron communication, it is becoming clear that neurotransmitters also affect glial cells. However, knowledge of neuron-to-glial signalling is limited. In this study, we examined the effects of the glutamate agonist N-methyl-D-aspartate (NMDA) on Müller cells, the predominant glia of the retina. Our immunocytochemical studies and immunodetection by Western blotting with monoclonal antibodies specific for the NMDAR1 subunit provided evidence for the expression by human Müller cells of this essential component of NMDA receptor-channels. Under conditions in which potassium currents were blocked, NMDA-induced currents could be detected in perforated-patch recordings from cultured and freshly dissociated human Müller cells. These currents were inhibited by competitive and non-competitive blockers of NMDA receptor-channels. Extracellular magnesium reduced the NMDA-activated currents in a voltage-dependent manner. However, despite a partial block by magnesium, Müller cells remained responsive to NMDA at the resting membrane potential. Under assay conditions not blocking K+ currents, exposure of Müller cells to NMDA was associated with an MK-801 sensitive inhibition of the inward-rectifying K+ current (IK(IR)), the largest current of these glia. This inhibitory effect of NMDA appears to be mediated by an influx of calcium since the inhibition of IK(IR) was significantly reduced when calcium was removed from the bathing solution or when the Müller cells contained the calcium chelator, BAPTA. Inhibition of the Müller cell KIR channels by the neurotransmitter glutamate is likely to have significant functional consequences for the retina since these ion channels are involved in K+ homeostasis, which in turn influences neuronal excitability.

We recently proposed a model of cytogenesis which assumes that primitive ancestral mammals and premammalian vertebrates had a retinal composition that consisted of about seven neurons per Müller cell, comprising 1–2 cone photoreceptors, 1–2 rod photoreceptors, 2–3 bipolar cells, 1–2 amacrine cells, less than 1 ganglion cell, and less than 1 horizontal cell (Reichenbach & Robinson, 1995). The Australian lungfish (Neoceratodus forsten) closely resembles the lobe-finned ancestors of land vertebrates, and has an extremely plesiomorphic nervous system. The present study, therefore, has examined the relative frequencies of retinal neurons and Müller cells (identified by immunolabelling for glutamine synthetase) in the lungfish retina. It was found that for each Müller cell there is an average of 1.9 cone photoreceptors, 1.7 rod photoreceptors, 3.1 amacrine/bipolar/horizontal cells, and 0.6 ganglion cells; amounting to a ratio of 7.3 neurons per Müller cell. These results support our conjecture that the sequence of cytogenesis in mammals is constrained by a developmental program that predates the evolution of mammals. The study also provides the first detailed morphological descriptions of lungfish Müller cells and their relationship with adjacent neurons. It was found that individual Müller cells in lungfish have a volume (more than 12,000 μm3) that is an order of magnitude higher than in mammals, yet the proportion of total retinal volume occupied by these cells (20%) is very similar.

Taurine immunoreactivity (IR) in 1 -μm sections of glutaraldehyde-fixed human optic nerve was observed using light microscopy and an antibody raised in rabbit to taurine conjugated to bovine serum albumin. Throughout the nerve, taurine-lR was prominent in glial cells, in their perinuclear regions, and in their numerous branching processes, some of which extended to the pial septa. The peripheral glial mantle (glia limitans) was densely stained, whereas axons and the pial septa showed relatively little or no taurine-IR. Immunoreactivity for glial fibrillary acidic protein (GFAP), an astrocyte-specific marker, was evaluated on adjacent sections. The pattern of GFAP-IR was highly similar to that for taurine, suggesting that a subset of taurine-immunoreactive glial cells are optic nerve astrocytes. To our knowledge, this is the first localization of taurine and GFAP in human optic nerve.

Synapse development and remodeling are regulated by a plethora of molecules such as receptor tyrosine kinases (RTKs), a family of cell surface receptors that play critical roles in neural development. Two families of RTKs implicated in synaptic functions, ErbBs and Ephs, share similar characteristics in terms of exhibiting forward and reverse signaling. In this review, we will discuss the latest advances in the functions of ErbBs and Ephs at the synapse, including dendritic spine morphogenesis, synapse formation and maturation, and synaptic transmission and plasticity. In addition to signaling at interneuronal synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions. Studies on RTKs and their cognate ligands in glial cells enhance our understanding on the nature of ‘tripartite synapse’. Implications of these signaling events in human diseases will be discussed.

Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells in a cell-type-specific and activity-dependent manner. During development, ECM plays crucial roles in proliferation, migration and differentiation of neural cells. In the mature brain, ECM undergoes a slow turnover and supports multiple physiological processes, while restraining structural plasticity. In the first part of this review, we discuss the contribution of ECM molecules to different forms of plasticity, including developmental plasticity in the cortex, long-term potentiation and depression in the hippocampus, homeostatic scaling of synaptic transmission and metaplasticity. In the second part, we focus on pathological changes associated with epileptogenic mutations in ECM-related molecules or caused by seizure-induced remodeling of ECM. The available data suggest that ECM components regulating physiological plasticity are also engaged in different aspects of epileptogenesis, such as dysregulation of excitatory and inhibitory neurotransmission, sprouting of mossy fibers, granule cell dispersion and gliosis. At the end, we discuss combinatorial approaches that might be used to counteract seizure-induced dysregulation of both ECM molecules and extracellular proteases. By restraining ECM modification and preserving the status quo in the brain, these treatments might prove to be valid therapeutic interventions to antagonize the progression of epileptogenesis.

During development, multipotent neural precursors give rise to oligodendrocyte progenitor cells (OPCs), which migrate and divide to produce additional OPCs. Near the end of embryogenesis and during postnatal stages, many OPCs stop dividing and differentiate as myelinating oligodendrocytes, whereas others persist as nonmyelinating cells. Investigations of oligodendrocyte development in mice indicated that the Nkx2.2 transcription factor both limits the number of OPCs that are formed and subsequently promotes their differentiation, raising the possibility that Nkx2.2 plays a key role in determining myelinating versus nonmyelinating fate. We used in vivo time-lapse imaging and loss-of-function experiments in zebrafish to further explore formation and differentiation of oligodendrocyte lineage cells. Our data show that newly specified OPCs are heterogeneous with respect to gene expression and fate. Whereas some OPCs express the nkx2.2a gene and differentiate as oligodendrocytes, others that do not express nkx2.2a mostly remain as nonmyelinating OPCs. Similarly to mouse, loss of nkx2.2a function results in excess OPCs and delayed oligodendrocyte differentiation. Notably, excess OPCs are formed as a consequence of prolonged OPC production from neural precursor cells. We conclude that Nkx2.2 promotes timely specification and differentiation of myelinating oligodendrocyte lineage cells from species representing different vertebrate taxa.

A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.