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Methamphetamine Effects on Prefrontal Cortical PV+ Interneurons and Resulting Cognitive Deficits

甲基苯丙胺对前额皮质 PV 中间神经元的影响及由此产生的认知缺陷

基本信息

批准号：
10669130
负责人：
ANTONIETA LAVIN
金额：
$ 35.86万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669130
关键词：
Acute Anxiety Attention Bathing Behavior Biological Markers Brain Chronic Cognitive Cognitive deficits Cues Data Disease Dopamine D1 Receptor Electrophysiology (science)Equilibrium Executive Dysfunction Face Functional disorder Genetic Goals Impaired cognition Impulsivity Interneurons Knowledge Literature Maintenance Mediating Medical Memory impairment Mental Depression Methamphetamine Methamphetamine dependence N-Methylaspartate Neurodevelopmental Disorder Parvalbumins Pathologic Pathology Pharmaceutical Preparations Play Prefrontal Cortex Preparation Psychoses Rat Transgene Rattus Reagent Receptor Activation Receptor Signaling Research Rodent Role Schizophrenia Self Administration Short-Term Memory Slice Social Functioning Stimulus Study models Substance Use Disorder Symptoms Synapses Synaptic Transmission Techniques Testing Viral Whole-Cell Recordings addiction antagonist autism spectrum disorder behavior test cell type cognitive disability cognitive function effective therapy executive function experimental study frontal lobe hippocampal pyramidal neuron insight interest knock-down methamphetamine abuse methamphetamine effect neuropsychiatric disorder neuropsychiatry novel novel therapeutic intervention pharmacologic psychostimulant receptor function theories tool transmission process

项目摘要

Project Summary Neuropsychiatric disorders are a very serious medical and societal problem with many different origins, however, a common and prevalent deficit found in these disorders is hypofrontality. Emerging theories posit that hypofrontality [alterations in the ratio of excitatory (E) and inhibitory (I) synaptic transmission] underlie schizophrenia, anxiety, addiction, autism spectrum disorders and depression. Methamphetamine (METH) addicts frequently develop hypofrontality and deficits in working memory (WM), attention, and impulsivity. Similarly, in rodents, repeated psychostimulant administration or self- administration elicits hypofrontality, WM deficits, psychosis-like behaviors, decreased interest in external stimuli and surroundings, and decreased social functioning, suggesting that psychostimulant administration in rodents represents a strong, face-valid model for studying the basic brain mechanisms that underlie hypofrontality and cognitive disabilities in METH addiction. The overall objective of the proposed studies is to identify the effects of METH-SA on the activity of cortical parvalbumin positive fast spiking interneurons (PV+FSIs) and the resulting changes in E-I ratio. The central hypothesis- informed by strong preliminary data and literature- is that METH treatment elicits cognitive deficits due to an increase in GABAergic synaptic transmission in the PFC via D1R activation of PV+FSIs. The proposal’s rationale is that the experiments will yield fundamental knowledge pertaining to the understanding of the cellular and synaptic mechanisms underlying hypofrontality induced by METH and will provide new insights into the basic mechanisms governing E-I balance in the prefrontal cortex. We will test the central hypothesis by pursuing the following specific aims: Aim 1 will determine the role of PV+FSIs in METH- induced cognitive deficits. Aim 2 will determine whether D1R signaling in PFC PV+FSIs is required for METH- induced enhancements of GABAergic transmission. Aim 3 will determine whether D1R signaling in PFC PV+FSIs is required for METH SA-induced cognitive deficits and METH reinstatement. The proposed research is significant because it will fill a fundamental gap in knowledge pertaining to the mechanisms underlying hypofrontality in METH-addiction and the effects of the psychostimulant in the activity of cortical PV+FSIs. Furthermore, the knowledge obtained from the proposed experiments will help to develop effective treatments to ameliorate drug-related cognitive deficits and can provide new insights into the basic mechanisms underlying hypofrontality in other neuropsychiatric conditions.

项目总结