Document text
Principal Investigator: Bridget Matikainen-Ankney
Organization: RUTGERS, THE STATE UNIV OF N.J.
Fiscal Year: 2024
Award: $151,492
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary/Abstract.
Despite the prevalence of obesity in the United States, how obesity strengthens brain circuits that reinforce
feeding is not known. This K01 proposal will identify specific neural circuits and subcircuit mechanisms that
enhance feeding and are co-opted in obesity. While prior research has focused on obesity-linked adaptations
in brain regions that drive homeostatic feeding, adaptations in brain regions involved in hedonic, motivated
feeding may be dysregulated in obesity and contribute to ongoing food seeking and weight gain. For instance,
the nucleus accumbens (NAc) is a brain region that regulates feeding and reward, and human and rodent
literature have revealed alterations in NAc activity in obesity, along with disrupted NAc synaptic plasticity
mechanisms. Preliminary data in this proposal demonstrates that NAc activity was selectively increased in a
subpopulation of neurons known to invigorate reward, D1-receptor expressing neurons (D1SPNs), in obese mice
during food seeking. Further, inhibiting NAc D1SPNs output decreased food seeking and prevented diet-induced
weight gain. Enhanced D1SPN activity was driven by increased intrinsic excitability and pre-synaptic
glutamatergic drive. Together these data suggest a model in which enhanced excitatory NAc inputs drive food
seeking in obesity. Yet it remains unclear which input(s) is/are responsible for increased NAc activity in obese
mice, whether all NAc D1SPNs are aberrantly activated or if select ensembles drive food seeking, and lastly,
what synaptic mechanisms underlie these adaptations. The central hypothesis of this proposal is that
enhanced excitatory input to NAc D1SPNs drives food seeking and obesity through attenuated synaptic
depression of glutamatergic inputs. The experiments outlined here will use in vivo optogenetics,
electrophysiology, genetic manipulations, novel operant behavioral paradigms, and a mouse model of diet-
induced obesity to test this hypothesis in the following Aims: Aim 1 will determine which NAc input(s) drive food
seeking and weight gain in obese mice. Aim 2 will investigate how select ensembles of NAc D1SPNs that are
activated during food seeking drive enhanced feeding in obesity. Aim 3 will define a potential mechanism
underlying changes in NAc plasticity in obese mice, and determine how such plasticity underlies food seeking
and weight gain. Together, these experiments represent a major step forward towards understanding how
obesity alters brain circuits, and why it so difficult for people to lose weight and keep it off.
Terms: <21+ years old><Adult><Adult Human><Affect><American><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Attenuated><Behavior><Behavioral Paradigm><Brain><Brain Nervous System><Brain region><CRISPR><CRISPR/Cas system><Calcium><Cancers><Cell Body><Cells><Clustered Regularly Interspaced Short Palindromic Repeats><Code><Coding System><Cornu Ammonis><D1 receptor><Data><Development><Diet><Disease><Disorder><Dopamine D1 Receptor><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalon><Food><Functional disorder><Glutamates><Goals><Head><Hippocampus><Human><Image><Impairment><In vivo two-photon calcium imaging><Individual><L-Glutamate><Lead><Leanness><Link><Literature><Long-Term Depression><Long-Term Synaptic Depression><Malignant Neoplasms><Malignant Tumor><Mediating><Mental disorders><Mental health disorders><Mentors><Mentorship><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Microscope><Mission><Modeling><Modern Man><Molecular><Motivation><Murine><Mus><NIDDK><National Institute of Diabetes and Digestive and Kidney Diseases><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus Accumbens><Obese Mice><Obesity><Opiate Receptors><Opioid Receptor><Output><Pb element><Persons><Physiopathology><Population><Postdoc><Postdoctoral Fellow><Prevalence><Property><Psychiatric Disease><Psychiatric Disorder><Public Health><Receptor Protein><Research><Research Associate><Research Support><Research Training><Rewards><Rodent><Rodentia><Rodents Mammals><Source><Subgroup><Synapses><Synaptic><Synaptic plasticity><System><Technical Expertise><Testing><Thalamic structure><Thalamus><Thesaurismosis><Thinness><Training><United States><Virus><Weight><Weight Gain><Weight Increase><adiposity><adulthood><amygdaloid nuclear complex><attenuate><attenuates><body weight gain><body weight increase><brain based><cardiac disease risk><cardiac disorder risk><career><cell type><corpulence><developmental><diet-associated obesity><diet-induced obesity><diet-related obesity><diets><effective therapy><effective treatment><electrophysiological><experience><experiment><experimental research><experimental study><experiments><feeding><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glutamatergic><heart disease risk><heart disorder risk><heavy metal Pb><heavy metal lead><hedonic><hippocampal><imaging><in vivo><in vivo calcium imaging><interest><knock-down><knockdown><longterm depression><longterm synaptic depression><malignancy><member><mental illness><metabolic rate><metabolism disorder><mouse model><mu opioid receptors><multidisciplinary><murine model><neoplasm/cancer><neural><neural circuit><neural circuitry><neural imaging><neural mechanism><neuro-imaging><neurocircuitry><neuroimaging><neurological imaging><neuromechanism><neuronal><novel><ob/ob mouse><obesity intervention><obesity therapy><obesity treatment><optogenetics><pathophysiology><post-doc><post-doctoral><post-doctoral trainee><presynaptic><prevent><preventing><programs><psychiatric illness><psychological disorder><receptor><research associates><reward processing><synapse><synaptic circuit><synaptic circuitry><synaptic depression><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><technical skills><thalamic><weights><wt gain><μ opioid receptors><μ-OR><μOR>