Dataset Information

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

ABSTRACT: BACKGROUND:The mediodorsal thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. Maintaining the proper balance between excitation and inhibition (E/I balance) is of principal importance for organizing cortical activity. Furthermore, the PFC E/I balance has been implicated in successful execution of multiple PFC-dependent behaviors in both animal research and the context of human psychiatric disorders. METHODS:Here, we used a pharmacogenetic strategy to decrease mediodorsal thalamic activity in adult male rats and evaluated the consequences for E/I balance in PFC pyramidal neurons as well as cognition, social interaction, and anxiety. RESULTS:We found that dampening mediodorsal thalamic activity caused significant reductions in gamma-aminobutyric acidergic signaling and increased E/I balance in the mPFC and was concomitant with abnormalities in these behaviors. Furthermore, by selectively activating parvalbumin interneurons in the mPFC with a novel pharmacogenetic approach, we restored gamma-aminobutyric acidergic signaling and E/I balance as well as ameliorated all behavioral impairments. CONCLUSIONS:These findings underscore the importance of thalamocortical activation of mPFC gamma-aminobutyric acidergic interneurons in a broad range of mPFC-dependent behaviors. Furthermore, they highlight this circuitry as a platform for therapeutic investigation in psychiatric diseases that involve impairments in PFC-dependent behaviors.

SUBMITTER: Ferguson BR

PROVIDER: S-EPMC5862785 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

Ferguson Brielle R BR Gao Wen-Jun WJ

Biological psychiatry 20171207 8

<h4>Background</h4>The mediodorsal thalamus plays a critical role in cognition through its extensive innervation of the medial prefrontal cortex (mPFC), but how the two structures cooperate at the single-cell level to generate associated cognitive functions and other mPFC-dependent behaviors remains elusive. Maintaining the proper balance between excitation and inhibition (E/I balance) is of principal importance for organizing cortical activity. Furthermore, the PFC E/I balance has been implicat ...[more]

PMID: 29373121

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Project description:Humans require a plethora of higher cognitive skills to perform executive functions, such as reasoning, planning, language and social interactions, which are regulated predominantly by the prefrontal cortex. The prefrontal cortex comprises the lateral, medial and orbitofrontal regions. In higher primates, the lateral prefrontal cortex is further separated into the respective dorsal and ventral subregions. However, all these regions have variably been implicated in several fronto-subcortical circuits. Dysfunction of these circuits has been highlighted in vascular and other neurocognitive disorders. Recent advances suggest the medial prefrontal cortex plays an important regulatory role in numerous cognitive functions, including attention, inhibitory control, habit formation and working, spatial or long-term memory. The medial prefrontal cortex appears highly interconnected with subcortical regions (thalamus, amygdala and hippocampus) and exerts top-down executive control over various cognitive domains and stimuli. Much of our knowledge comes from rodent models using precise lesions and electrophysiology readouts from specific medial prefrontal cortex locations. Although, anatomical disparities of the rodent medial prefrontal cortex compared to the primate homologue are apparent, current rodent models have effectively implicated the medial prefrontal cortex as a neural substrate of cognitive decline within ageing and dementia. Human brain connectivity-based neuroimaging has demonstrated that large-scale medial prefrontal cortex networks, such as the default mode network, are equally important for cognition. However, there is little consensus on how medial prefrontal cortex functional connectivity specifically changes during brain pathological states. In context with previous work in rodents and non-human primates, we attempt to convey a consensus on the current understanding of the role of predominantly the medial prefrontal cortex and its functional connectivity measured by resting-state functional MRI in ageing associated disorders, including prodromal dementia states, Alzheimer's disease, post-ischaemic stroke, Parkinsonism and frontotemporal dementia. Previous cross-sectional studies suggest that medial prefrontal cortex functional connectivity abnormalities are consistently found in the default mode network across both ageing and neurocognitive disorders such as Alzheimer's disease and vascular cognitive impairment. Distinct disease-specific patterns of medial prefrontal cortex functional connectivity alterations within specific large-scale networks appear to consistently feature in the default mode network, whilst detrimental connectivity alterations are associated with cognitive impairments independently from structural pathological aberrations, such as grey matter atrophy. These disease-specific patterns of medial prefrontal cortex functional connectivity also precede structural pathological changes and may be driven by ageing-related vascular mechanisms. The default mode network supports utility as a potential biomarker and therapeutic target for dementia-associated conditions. Yet, these associations still require validation in longitudinal studies using larger sample sizes.

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Dataset Information

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

Publications

Thalamic Control of Cognition and Social Behavior Via Regulation of Gamma-Aminobutyric Acidergic Signaling and Excitation/Inhibition Balance in the Medial Prefrontal Cortex.

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