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Principal Investigator: Moriel Zelikowsky
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $571,982
Funding agency: National Institute of Mental Health
PROJECT SUMMARY/ ABSTRACT
Extended deprivation of social contact can produce deleterious effects on the brain and behavior. Social isolation
(SI), or its perception (loneliness), is as predictive a risk factor for poor health outcomes as smoking or obesity.
Many factors have contributed to a modern epidemic of loneliness: a growing aging population, dramatic changes
to our social structure (technology, social media), the opioid crisis, and, most recently, the COVID-19 pandemic.
One of the most damaging impacts of SI is the promotion of interpersonal aggression and violence against others
– indeed, SI-associated domestic violence has risen by 20%, rates of suicide have surged, and school shootings
continue to rip at the fabric of society. Despite this, we have a poor understanding of the genetically-defined,
circuit mechanisms that give rise to isolation-induced aggression, representing a critical barrier for the
development of targeted interventions and cognitive therapies to treat pathological forms of aggression. One key
brain region known to exert top-down, cognitive control over behavior, including aggression, is the medial
prefrontal cortex (mPFC). However, the role of the mPFC in modulating the effects of SI-induced aggression is
unknown. In the project proposed here, we will interrogate the function of distinct, genetically-defined cells in the
mPFC to modulate SI-induced aggression. In support of this, we recently identified the neuropeptide Tachykinin
2 (Tac2)/Neurokinin B (NkB) as a key, subcortical mediator of SI. Here, we will test whether Tac2 signaling in
the mPFC exerts cortical control of SI-aggression. In preliminary studies, we have discovered that Tac2+ mPFC
neurons comprise a unique, unexplored class of GABAergic interneurons (INs). These findings lead to the
specific hypothesis that Tac2+ INs exert feed-forward inhibition of excitatory pyramidal neurons (PNs) to mediate
SI-aggression. To test this, we will combine behavior, machine learning, molecular-genetic loss- and gain-of
function manipulations, and in vivo Ca2+ imaging to achieve a circuit-level, mechanistic understanding of how
distinct populations of genetically-defined neurons in the mPFC exert coordinated, cortical control of SI-
aggression. We will determine whether mPFC Tac2+ neurons are required for SI-aggression (Aim 1), whether
mPFC PNs are sufficient to inhibit SI-aggression (Aim 2), and whether Tac2+ INs directly regulate PN activity
during SI-aggression (Aim 3). Collectively, we aim to uncover a conserved, genetically-defined mPFC
microcircuit for the top-down, cortical control of isolation-induced aggression. These findings will transform the
field by expanding our understanding of how pathological forms of aggression are encoded and controlled by
prefrontal circuits in the brain. Importantly, this research will have profound implications for the treatment of social
isolation-related mental health disorders, particularly those that result in violence.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Aggression><Aggressive behavior><Aminalon><Aminalone><Assay><Behavior><Bioassay><Biological Assay><Brain><Brain Nervous System><Brain region><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cognition Therapy><Cognitive Psychotherapy><Cognitive Therapy><Cognitive treatment><Color><Connector Neuron><Coupled><Data><Development><Domestic Violence><Encephalon><Endoscopy><Epidemic><GABA><House mice><Housing><Hypothalamic structure><Hypothalamus><Image><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Lead><Loneliness><Machine Learning><Medial><Mediating><Mediator><Mental disorders><Mental health disorders><Mice><Mice Mammals><Modernization><Molecular Genetics><Murine><Mus><Mus musculus><NK-3 Receptors><NK3 Receptor><NK3R><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurokinin B><Neurokinin B Receptor><Neurokinin B Receptors><Neurokinin beta><Neurokinin-3 Receptors><Neuromedin K><Neuromedin K Receptor><Neurons><Neuropeptides><Obesity><Pathologic><Pb element><Perception><Population><Prefrontal Cortex><Psychiatric Disease><Psychiatric Disorder><Public Health><Pyramidal neuron><Research><Risk Factors><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Transduction><Signal Transduction Systems><Signaling><Smoking><Social Controls><Social isolation><Socialization><Societies><System><Tachykinin><Technology><Testing><Textiles><Therapeutic Intervention><Violence><adiposity><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><attenuation><behavior test><behavioral test><biological signal transduction><cognitive behavior intervention><cognitive behavior modification><cognitive behavior therapy><cognitive behavioral intervention><cognitive behavioral modification><cognitive behavioral therapy><cognitive behavioral treatment><cognitive control><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><corpulence><developmental><endoscopic imaging><fabric><gain of function><gamma-Aminobutyric Acid><gene function><heavy metal Pb><heavy metal lead><hippocampal pyramidal neuron><hypothalamic><imaging><in vivo><intervention therapy><lonely><loss of function><machine based learning><mental illness><neural><neural patterning><neuronal><opiate crisis><opioid crisis><opioid epidemic><optogenetics><poor health outcome><population aging><psychiatric illness><psychological disorder><reduced health outcome><school shooting><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social><social contact><social deprivation><social group><social media><social role><social structural><social structure><socio-structural><sociostructural><suicide rate><violent><violent behavior><worse health outcome><γ-Aminobutyric Acid>