Neuroscience
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Dysregulated cholinergic neurotransmission has been implicated in the pathophysiology of schizophrenia, particularly negative symptoms and cognitive deficits. The aim of the present study was to evaluate the role of neocortical cholinergic innervation and of the N-methyl-d-aspartate (NMDA) receptor antagonist phencyclidine (PCP) on social interaction and novel object recognition (NOR), a declarative memory task. The cholinergic corticopetal projection was lesioned by local infusion of the immunotoxin 192 IgG-saporin into nucleus basalis magnocellularis of adult male Lister hooded rats. ⋯ Animals with severe cortical cholinergic hypofunction maintain the ability to perform in a declarative memory test, although the task is carried out less intensively. However, a provocation of psychosis-like behavior by a dose of PCP that does not by itself impair performance in normal animals, will abolish the ability to recognize novel objects in animals lacking cortical cholinergic innervation. The present findings support a possible role for cortical cholinergic hypofunction in the negative and cognitive symptoms of schizophrenia, and the potential for cholinergic augmentation as part of the pharmacological profile of antipsychotic drugs.
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GABAergic neurons of the medial septum of the basal forebrain make up a substantial portion of the septo-hippocampal pathway fibers, and are known to modulate hippocampal amino acid neurotransmission and support cognitive function. Importantly, these neurons are also implicated in age-related cognitive decline. Hypothalamic orexin/hypocretin neurons innervate and modulate the activity of these basal forebrain neurons and also provide direct inputs to the hippocampus. ⋯ Furthermore, immunohistochemical characterization of the medial septum revealed a significant decrease in parvalbumin (PV)-positive cell bodies in aged animals, and a significant reduction in orexin fiber innervation to the remaining GABAergic cells within the septum, while orexin innervation to the hippocampus was unaltered by the aging process. These findings indicate that: (1) OxA directly modulates hippocampal amino acid neurotransmission in young animals, (2) Aged animals show enhanced responsivity to exogenous OxA activation of the septo-hippocampal pathway, and (3) Aged animals undergo an intrinsic reduction in medial septum PV-immunoreactivity and a decrease in orexin innervation to remaining septal PV neurons. Alterations in orexin regulation of septo-hippocampal activity may contribute to age-related dysfunctions in arousal, learning, and memory.