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The medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.

ABSTRACT: Cognitive flexibility deficits are one of the most pervasive symptoms across psychiatric disorders, making continued investigation of the circuitry underlying this function a top priority. Medial septum (MS) lesions lead to perseverative, inflexible-type behavior; however, a role for this region in cognitive flexibility circuitry has never been examined. We activated the MS (DREADDs) and measured performance in a T-maze spatial reversal learning task in male Sprague-Dawley rats. Systemic activation of the MS (CNO) significantly decreased both trials to perform a reversal and entries into the previously baited arm. Intra-ventral subiculum CNO enhanced reversal learning in the same manner as systemic CNO and also significantly increased ventral tegmental area and decreased substantia nigra dopamine neuron population activity. Finally, co-injection of the D1 antagonist SCH23390 with CNO prevented the enhanced reversal learning performance seen in the previous two experiments. Taken together, these data suggest a key role for the MS in cognitive flexibility, and suggest that MS-mediated changes in midbrain dopamine neuron population activity could be one mechanism by which this occurs.

SUBMITTER: Bortz DM

PROVIDER: S-EPMC6898642 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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The medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.

Bortz D M DM Gazo K L KL Grace A A AA

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190701 13

Cognitive flexibility deficits are one of the most pervasive symptoms across psychiatric disorders, making continued investigation of the circuitry underlying this function a top priority. Medial septum (MS) lesions lead to perseverative, inflexible-type behavior; however, a role for this region in cognitive flexibility circuitry has never been examined. We activated the MS (DREADDs) and measured performance in a T-maze spatial reversal learning task in male Sprague-Dawley rats. Systemic activat ...[more]

PMID: 31261368

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Project description:Perturbations in metabolism are a well-documented but complex facet of schizophrenia pathology. Optimal cellular performance requires the proper functioning of the electron transport chain, which is constituted by four enzymes located within the inner membrane of mitochondria. These enzymes create a proton gradient that is used to power the enzyme ATP synthase, producing ATP, which is crucial for the maintenance of cellular functioning. Anomalies in a single enzyme of the electron transport chain are sufficient to cause disruption of cellular metabolism. The last of these complexes is the cytochrome c oxidase (COX) enzyme, which is composed of thirteen different subunits. COX is a major site for oxidative phosphorylation, and anomalies in this enzyme are one of the most frequent causes of mitochondrial pathology. The objective of the present report was to assess if metabolic anomalies linked to COX dysfunction may contribute to substantia nigra/ventral tegmental area (SN/VTA) pathology in schizophrenia. We tested COX activity in postmortem SN/VTA from schizophrenia and non-psychiatric controls. We also tested the protein expression of key subunits for the assembly and activity of the enzyme, and the effect of antipsychotic medication on subunit expression. COX activity was not significantly different between schizophrenia and non-psychiatric controls. However, we found significant decreases in the expression of subunits II and IV-I of COX in schizophrenia. Interestingly, these decreases were observed in samples containing the entire rostro-caudal extent of the SN/VTA, while no significant differences were observed for samples containing only mid-caudal regions of the SN/VTA. Finally, rats chronically treated with antipsychotic drugs did not show significant changes in COX subunit expression. These findings suggest that COX subunit expression may be compromised in specific sub-regions of the SN/VTA (i.e. rostral regions), which may lead to a faulty assembly of the enzyme and a greater vulnerability to metabolic insult.

Dataset Information

The medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.

Publications

The medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons.

Similar Datasets

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