Dataset Information

Hippocampal circuit dysfunction in psychosis.

ABSTRACT: Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate striatal dopamine function, such as the hippocampus. This review draws together these recent data to discuss why the hippocampus may be especially vulnerable in the pathophysiology of psychosis. First, we describe the neurodevelopmental trajectory of the hippocampus and its susceptibility to dysfunction, exploring this region's proneness to structural and functional imbalances, metabolic pressures, and oxidative stress. We then examine mechanisms of hippocampal dysfunction in psychosis and in individuals at high-risk for psychosis and discuss how and when hippocampal abnormalities may be targeted in these groups. We conclude with future directions for prospective studies to unlock the discovery of novel therapeutic strategies targeting hippocampal circuit imbalances to prevent or delay the onset of psychosis.

SUBMITTER: Knight S

PROVIDER: S-EPMC9411597 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Hippocampal circuit dysfunction in psychosis.

Knight Samuel S McCutcheon Robert R Dwir Daniella D Grace Anthony A AA O'Daly Owen O McGuire Philip P Modinos Gemma G

Translational psychiatry 20220825 1

Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate st ...[more]

PMID: 36008395

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Project description:Temporal lobe epilepsy, a chronic disease of the brain characterized by degeneration of the hippocampus, has impaired risk assessment. Risk assessment is vital for survival in complex environments with potential threats. However, the underlying mechanisms remain largely unknown. The intricate balance of gene regulation and expression across different brain regions is related to the structure and function of specific neuron subtypes. In particular, excitation/inhibition imbalance caused by hyperexcitability of glutamatergic neurons and/or dysfunction of GABAergic neurons, have been implicated in epilepsy. First, we estimated the risk assessment (RA) by evaluating the behavior of mice in the center of the elevated plus maze, and found that the kainic acid-induced temporal lobe epilepsy mice were specifically impaired their RA. This experiment evaluated approach-RA, with a forthcoming approach to the open arm, and avoid-RA, with forthcoming avoidance of the open arm. Next, results from free-moving electrophysiological recordings showed that in the hippocampus, ∼7% of putative glutamatergic neurons and ∼15% of putative GABAergic neurons were preferentially responsive to either approach-risk assessment or avoid-risk assessment, respectively. In addition, ∼12% and ∼8% of dorsal lateral septum GABAergic neurons were preferentially responsive to approach-risk assessment and avoid-risk assessment, respectively. Notably, during the impaired approach-risk assessment, the favorably activated dorsal dentate gyrus and CA3 glutamatergic neurons increased (∼9%) and dorsal dentate gyrus and CA3 GABAergic neurons decreased (∼7%) in the temporal lobe epilepsy mice. Then, we used RNA sequencing and immunohistochemical staining to investigate which subtype of GABAergic neuron loss may contribute to excitation/inhibition imbalance. The results show that temporal lobe epilepsy mice exhibit significant neuronal loss and reorganization of neural networks. In particular, the dorsal dentate gyrus and CA3 somatostatin-positive neurons and dorsal lateral septum cholecystokinin-positive neurons are selectively vulnerable to damage after temporal lobe epilepsy. Optogenetic activation of the hippocampal glutamatergic neurons or chemogenetic inhibition of the hippocampal somatostatin neurons directly disrupts RA, suggesting that an excitation/inhibition imbalance in the dHPC dorsal lateral septum circuit results in the impairment of RA behavior. Taken together, this study provides insight into epilepsy and its comorbidity at different levels, including molecular, cell, neural circuit, and behavior, which are expected to decrease injury and premature mortality in patients with epilepsy.

Project description:BackgroundPostoperative cognitive dysfunction (POCD) is a prevalent complication following anesthesia and surgery, particularly in the elderly, leading to increased mortality and reduced quality of life. Despite its prevalence, there are no effective clinical treatments. Exercise has shown cognitive benefits in aging and various diseases, which can be transferred to sedentary animals through plasma. However, it is unclear if exercise-conditioned plasma can replicate these benefits in the context of POCD.MethodsSixteen-month-old male C57BL/6J mice underwent 30 days of voluntary running wheel training or received systemic administration of exercise-conditioned plasma, followed by tibial fracture surgery under general anesthesia at 17 months of age. Cognitive performance, hippocampal synaptic deficits, neuroinflammation, BDNF/TrkB signaling, and medial septum (MS)-hippocampal cholinergic activity were evaluated through immunohistochemical staining, transmission electron microscopy, Western blotting, and biochemical assays. To investigate the role of hippocampal BDNF signaling and cholinergic activity in the therapeutic effects, the TrkB antagonist ANA-12 and the cholinergic receptor muscarinic 1 (CHRM1) antagonist trihexyphenidyl (THP) were administered via intraperitoneal injection, and adeno-associated virus (AAV) vectors expressing Chrm1 shRNA were delivered via intrahippocampal stereotaxic microinjection.ResultsExercise-conditioned plasma mimicked the benefits of exercise, alleviating cognitive decline induced by anesthesia/surgery, restoring hippocampal synapse formation and levels of regulators for synaptic plasticity, inhibiting neuroinflammatory responses to surgery by microglia and astrocytes, augmenting BDNF production and TrkB phosphorylation in hippocampal neurons, astrocytes, and microglia, upregulating MS expression of choline acetyltransferase (CHAT) and hippocampal expression of CHRM1 in neurons and astrocytes, and enhancing hippocampal cholinergic innervation and acetylcholine release. Conversely, ANA-12 administration blocked TrkB activation and reduced the protective effects on cognition, synaptic deficits, and neuroinflammatory reactivity of glial cells post-surgery. Similarly, THP administration or intrahippocampal delivery of AAV-Chrm1 shRNA inhibited the activation of the hippocampal cholinergic circuit by exercise plasma, negating the cognitive and neuropathological benefits and reducing BDNF/TrkB signaling enhancements.ConclusionExercise-conditioned plasma can replicate the protective effects of exercise against anesthesia/surgery-induced neuroinflammation, synaptic, and cognitive impairments, at least partly, through CHRM1-dependent regulation of hippocampal cholinergic activity and BDNF/TrkB signaling.

Dataset Information

Hippocampal circuit dysfunction in psychosis.

Publications

Hippocampal circuit dysfunction in psychosis.

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