Higher brain regions are more susceptible to global ischemia than the brainstem, but is there a gradual increase in vulnerability in the caudal-rostral direction or is there a discrete boundary? We examined the interface between `higher` thalamus and the hypothalamus the using live brain slices where variation in blood flow is not a factor. Whole-cell current clamp recording of 18 thalamic neurons in response to 10 min O2/glucose deprivation (OGD) revealed a rapid anoxic depolarization (AD) from which thalamic neurons do not recover. Newly acquired neurons could not be patched following AD, confirming significant regional thalamic injury. Coinciding with AD, light transmittance (LT) imaging during whole-cell recording showed an elevated LT front that initiated in midline thalamus and that propagated into adjacent hypothalamus. However, hypothalamic neurons patched in paraventricular nucleus (PVN, n= 8 magnocellular and 12 parvocellular neurons) and suprachiasmatic nucleus (SCN, n= 18) only slowly depolarized as AD passed through these regions. And with return to control aCSF, hypothalamic neurons repolarized and recovered their input resistance and action potential amplitude. Moreover, newly acquired hypothalamic neurons could be readily patched following exposure to OGD, with resting parameters similar to neurons not previously exposed to OGD. Thalamic susceptibility and hypothalamic resilience were also observed following ouabain exposure which blocks the Na+/K+ pump, evoking depolarization similar to OGD in all neuronal types tested. Finally, brief exposure to elevated [K+]o caused spreading depression (SD, a milder, AD-like event) only in thalamic neurons so SD generation is regionally correlated with strong AD. Therefore the thalamus-hypothalamus interface represents a discrete boundary where neuronal vulnerability to ischemia is high in thalamus (like more rostral neocortex, striatum, hippocampus). In contrast hypothalamic neurons are comparatively resistant, generating weaker and recoverable anoxic depolarization similar to brainstem neurons, possibly the result of a Na/K pump that better functions during ischemia.

1. Inflammatory bowel diseases (IBD) alter the function of the enteric nervous system and the sensory innervation of the gastrointestinal (GI) tract. Less is known about whether IBD also affects the sympathetic nervous system (SNS). Given the importance of the SNS in regulating GI function and possibly immune system activation, the present review examines the evidence of sympathetic dysfunction during IBD and its possible consequences. 2. Sympathetic axons within the GI tract innervate several cell types, including vascular myocytes, enteric neurons and immune cells. The major neurotransmitters released from sympathetic varicosities are noradrenaline, neuropeptide Y and ATP or a related purine. 3. Clinical studies of IBD patients have provided evidence of an association between IBD and axonal or demyelinating neuropathy. Assays of autonomic function suggest that ulcerative colitis and Crohn's disease, the two major forms of IBD, have contrasting effects on sympathetic neural activity. 4. Animal models of IBD have been used to examine the effects of these diseases on sympathetic neurophysiology. A decrease in the release of noradrenaline from sympathetic varicosities in inflamed and uninflamed regions of the GI tract has consistently been reported. Recent findings suggest that the decrease in neurotransmitter release may be due to inhibition of N-type voltage-gated Ca(2+) current in post-ganglionic sympathetic neurons. 5. Interest in the role of the SNS in IBD is rapidly increasing. However, much work needs to be done to enhance understanding of how SNS function is altered during IBD and what contribution, if any, these changes make to pathogenesis.

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Inflammation has profound effects on the innervation of affected tissues, including altered neuronal excitability and neurotransmitter release. As Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs) is a critical determinant of excitation-secretion coupling in nerve terminals, the aim of this study was to characterize the effect of overnight incubation in the inflammatory mediator tumour necrosis factor α (TNFα; 1 nm) on VGCCs in dissociated neurons from mouse superior mesenteric ganglia (SMG). Voltage-gated Ca 2+ currents (I Ca ) were measured using the perforated patch clamp technique and the VGCC subtypes present in SMG neurons were estimated based on inhibition by selective VGCC blockers: ω-conotoxin GVIA (300 nm; N-type), nifedipine (10 μm; L-type), and ω-conotoxin MVIIC (300 nm; N-, P/Q-type). We used intracellular Ca 2+ imaging with Fura-2 AM to compare Ca 2+ influx during depolarizations in control and TNFα-treated neurons. TNF receptor and VGCC mRNA expression were measured using PCR, and channel α subunit (CaV2.2) was localized with immunohistochemistry. Incubation in TNFα significantly decreased I Ca amplitude and depolarization-induced Ca

Extracellular purines play important roles as neurotransmitters and paracrine mediators in the gastrointestinal (GI) tract. Inflammation of the GI tract causes marked changes in the release and extracellular catabolism of purines, and can modulate purinoceptor expression and/or signaling. The functional consequences of this include suppression of the purinergic component of inhibitory neuromuscular and neurovascular transmission, increased release of purines from immune and epithelial cells, loss of enteric neurons to damage through P2X7 purinoceptors, and enhanced activation of pain fibres. The purinergic system represents an important target for drug therapies that may improve GI inflammation and its consequences.