The brain is composed of intricate circuits of neurons communicating via fast electrical signals created by the coordinated actions of excitatory and inhibitory neurotransmission. Overlaid on this broad structure is a diverse set of slower instructive chemical signaling, referred to collectively as neuromodulation, which critically regulate fast transmission and neuronal function. This proposal brings together molecular-genetic tools, expertise in manipulating and interrogating neuromodulatory neuronal circuits, imaging and electrophysiology to decipher neurohypophyseal regulation of dopaminergic neurons. Dopamine is an essential modulator, required for vertebrate life. Dopamine dysregulation, best studied in degenerative disease, is also associated with anxiety and mood disorders, as well as neurodevelopmental diseases and addiction. Oxytocin, a neurohypophyseal hormone and neuromodulator implicated in social affect and reproductive behaviors, interacts with reward systems indirectly, and also by directly regulating the tonic activity of dopamine neurons, as work from our laboratory has recently demonstrated. The control of dopamine signaling by neurohypophyseal peptides represents a powerful regulation of essential adaptive behaviors, which both emphasizes the central importance of these endogenous peptides in development and establishes them as therapeutic targets for ameliorating disease states. The objective for this proposal is to build on our preliminary data in order to better understand the mechanisms and context of direct neurohypophyseal control over DA neuron function. The major overall premise of this proposal is that neurohypophyseal peptides act centrally in midbrain dopaminergic regions regulating cellular activity, synaptic transmission, as well as plasticity, and that this regulation is sex-independent and important in early development. To address several hypotheses deriving from this premise, we synthesize anatomical, electrophysiological, and behavioral assays, with technical innovations ranging from new light-sheet imaging technologies to promoter-driven viruses for orthogonal control of multiple modulatory systems. Carrying out the proposed experiments would advance our conceptual understanding of the complex neuromodulatory systems regulating affect and reward, and it is relevant to numerous mental health, neurodevelopmental and neurodegenerative disorders characterized by dysfunctional neuromodulation.

Public Health Relevance

Neuromodulation is the complex, slower signaling that guides fast neurotransmission and alters how neural circuits operate in health and disease. Our project aims to reveal how neurohypophyseal peptides, in particular oxytocin, regulate the physiology and plasticity of dopamine neurons in males and females. Beyond the basic value of this work, the questions addressed by the proposal are highly relevant for autism, depression, anxiety, and addiction disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH117111-02
Application #
9762218
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Tonelli, Leonardo Heraldo
Project Start
2018-08-13
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201