No abstract

Weight gain is one side effect of many antipsychotic drugs (APDs). A small number of lateral hypothalamic/perifornical area (LH/PFA) neurons express the orexins, peptides that are critically involved in body weight regulation and arousal. We examined the ability of APDs to activate orexin neurons, as reflected by induction of Fos. APDs with significant weight gain liability increased Fos expression in orexin neurons, but APDs with low or absent weight gain liability did not. The weight gain liability of APDs was correlated with the degree of Fos induction in orexin neurons of the lateral LH/PFA. In contrast, amphetamine, which causes weight loss, increased Fos expression in orexin neurons of the medial but not lateral LH/PFA. We compared the effects of amphetamine and clozapine, an APD with weight gain liability, on orexin neurons innervating the prefrontal cortex. Clozapine induced Fos in 75% of the orexin neurons that project to the cortex, but amphetamine induced Fos in less than a third of these cells. These data suggest that APDinduced weight gain is associated with activation of distinct orexin neurons and emphasize the presence of anatomically and functionally heterogeneous populations of orexin neurons.

Depressive illness is associated with changes in amygdalar volume, and stressful life events are known to precipitate depressive episodes in this patient population. Stress affects amygdalar synaptic plasticity and several neurotransmitter systems have been implicated in stress-mediated changes in the brain, including the glutamatergic system. However, the role of the glutamatergic system in stress-mediated plasticity in the amygdala remains to be determined. Accordingly the current study examined the stress modulation of extracellular glutamate levels in the basolateral nucleus (BLA) and the central nucleus (CeA) of the amygdala by in vivo microdialysis. Acute stress increased extracellular glutamate levels in the BLA and CeA, although the dynamics of these stress-mediated changes were dramatically different in these amygdalar nuclei. Tetrodotoxin administration reduced basal, and completely eliminated stress-mediated increases in glutamate efflux in the amygdala, demonstrating that stress effects are dependent on local axonal depolarization. Moreover, stress-mediated increases in glutamate efflux in the BLA were inhibited by the antidepressant tianeptine but not by the selective serotonin-reuptake inhibitor fluoxetine. Collectively, these data demonstrate that stress-induced modulation of glutamate neurochemistry reflects a fundamental pathological change that may contribute to the aetiology and progression of depressive illness, and suggest that some antidepressants such as tianeptine may elicit their clinical effects by modulation of glutamatergic neurotransmission.

Aging is associated with impairments in learning and memory and a greater incidence of limbic seizures. These changes in the aged brain have been associated with increased excitability of hippocampal pyramidal cells caused by a reduced number of GABAergic interneurons. To better understand these issues, we performed cell counts of GABAergic interneurons and examined GABA efflux and GABAergic inhibition in area CA1 of the hippocampus of young (3-5 mo) and aged (26-30 mo) rats. Aging significantly reduced high K + /Ca 2+ -evoked GABA, but not glutamate efflux in area CA1. Immunostaining revealed a significant loss of GABAergic interneurons, but not inhibitory boutons in stratum oriens and stratum lacunosum moleculare. Somatostatinimmunoreactive oriens-lacunosum moleculare (O-LM) cells, but not parvalbumin-containing interneurons were selectively lost. O-LM cells project to distal dendrites of CA1 pyramidal cells, providing dendritic inhibition. Accordingly, inhibition of dendritic input to CA1 from entorhinal cortex was selectively reduced. These findings suggest that the age-dependent loss of interneurons impairs dendritic inhibition and dysregulates entorhinal cortical input to CA1, potentially contributing to cognitive impairment and seizures.

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of inflammatory proteins (IL-β, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1β, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

The basal forebrain cholinergic system (BFCS) plays a role in several aspects of attentional function. Activation of this system by different afferent inputs is likely to influence how attentional resources are allocated. While it has been recognized for some time that the hypothalamus is a significant source of projections to the basal forebrain, the phenotype(s) of these inputs and the conditions under which their regulation of the BFCS becomes functionally relevant are still unclear. The cell bodies of neurons expressing orexin/hypocretin neuropeptides are restricted to the lateral hypothalamus and contiguous perifornical area but have widespread projections, including to the basal forebrain. Orexin fibers and both orexin receptor subtypes are distributed in cholinergic parts of the basal forebrain, where application of orexin peptides increases cell activity and cortical acetylcholine release. Furthermore, disruption of orexin signaling in the basal forebrain impairs the cholinergic response to an appetitive stimulus. In this review, we propose that orexin inputs to the BFCS form an anatomical substrate for links between arousal and attention, and that these interactions might be particularly important as a means by which interoceptive cues bias allocation of attentional resources toward related exteroceptive stimuli. Dysfunction in orexin-acetylcholine interactions may play a role in the arousal and attentional deficits that accompany neurodegenerative conditions as diverse as drug addiction and age-related cognitive decline.

Aging is associated with many physiological alterations—such as changes in sleep patterns, metabolism and food intake—suggestive of hypothalamic dysfunction, but the effects of senescence on specific hypothalamic nuclei and neuronal groups that mediate these alterations is unclear. The lateral hypothalamus and contiguous perifornical area (LH/PFA) contains several populations of neurons, including those that express the neuropeptides orexin (hypocretin) or melanin-concentrating hormone (MCH). Collectively, orexin and MCH neurons influence many integrative homeostatic processes related to wakefulness and energy balance. Here, we determined the effect of aging on numbers of orexin and MCH neurons in young adult (3–4 months) and old (26–28 months) Fisher 344/Brown Norway F1 hybrid rats. Aged rats exhibited a loss of greater than 40% of orexin-immunoreactive neurons in both the medial and lateral (relative to the fornix) sectors of the LH/PFA. MCH-immunoreactive neurons were also lost in aged rats, primarily in the medial LH/PFA. Neuronal loss in this area was not global as no change in cells immunoreactive for the pan-neuronal marker, NeuN, was observed in aged rats. Combined with other reports of altered receptor expression or behavioral responses to exogenously-administered neuropeptide, these data suggest that compromised orexin (and, perhaps, MCH) function is an important mediator of age-related homeostatic disturbances of hypothalamic origin. The orexin system may represent a crucial substrate linking homeostatic and cognitive dysfunction in aging, as well as a novel therapeutic target for pharmacological or genetic restoration approaches to preventing or ameliorating these disturbances.

Exposure of rats to an odor of a predator can elicit an innate fear response. In addition, such exposure has been shown to activate limbic brain regions such as the amygdala. However, there is a paucity of data on the phenotypic characteristics of the activated amygdalar neurons following predator odor exposure. In the current experiments, rats were exposed to cloth which contained either ferret odor, butyric acid, or no odor for 30 minutes. Ferret odor-exposed rats displayed an increase in defensive burying versus control rats. Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with Ca2+/calmodulin-dependent protein kinase II (CAMKII), parvalbumin, or calbindin were made in the basolateral (BLA), central (CEA), and medial (MEA) nucleus of the amygdala. Dual-labeled immunohistochemistry showed a significant increase in the percentage of CAMKII–positive neurons also immunoreactive for c-Fos in the BLA, CEA and MEA of ferret odor-exposed rats compared to control and butyric acid-exposed groups. Further results showed a significant decrease in calbindin-immunoreactive neurons that were also c-Fos-positive in the anterior portion of the BLA of ferret odor-exposed rats compared to control and butyric acid-exposed rats, whereas the MEA expressed a significant decrease in calbindin/c-Fos dual-labeled neurons in butyric acid-exposed rats compared to controls and ferret odor-exposed groups. These results enhance our understanding of the functioning of the amygdala following exposure to predator threats by showing phenotypic characteristics of activated amygdalar neurons. With this knowledge, specific neuronal populations could be targeted to further elucidate the fundamental underpinnings of anxiety and could possibly indicate new targets for the therapeutic treatment of anxiety.