Mental disorders, including, obsessive-compulsive disorder (OCD), schizophrenia, and drug addiction are linked to pathology in the cortico-basal ganglia (BG), reward circuit. Not only do these illnesses have a common circuitry, but also they emerge relatively early in life. Infancy through young adulthood is the critical time in which incentive-based learning forms the basis for goal-directed behaviors. Consistent with this rapid behavioral development, the prefrontal cortical and striatal circuits undergo maturation and refinement. While the BG is thought to process information via parallel, segregated circuits, it's now recognized role in the learning process supports emerging data demonstrating integration between loops at specific locations. Our laboratory focuses on the anatomical circuitry of the reward system and the integrative aspects of cortico-basal ganglia information processing. During the previous funding period we: 1. Discovered that the prefrontal cortico-BG network combines topographical and non-topographical rules, linking distinct components of the cortical circuits in specific striatal and thalamic regions, creating nodal points of converging inputs. This provides the underlying circuits for information processing across functional domains. 2. We showed a unique connection between the lateral habenular nucleus (LHb) and the midbrain dopamine cells placing it in a position to inhibit propagation of the reward signal. 3. We demonstrated profound cell proliferation throughout the striatum during the first postnatal year that is significantly higher in the ventral striatum compared to other striatal areas. These new cells are predominately a subpopulation of glia cells, which are thought to play a role in long-term potentiation. Our hypothesis is that nodal points of convergent prefrontal cortex (PFC) inputs to the striatum also interface with inputs from the amygdala and hippocampal formation. We also hypothesize that inputs to the LHb are derived, via the pallidum, from striatal regions that receive convergent cortical projections. The experiments proposed here will test these hypotheses by: 1. Delineating the nodal points of convergent inputs from the PFC, amygdala, and temporal cortex;2. Examining the place of the habenular n. in the reward circuit and its association with the integrative network. The most active periods of incentive-based learning occurs during childhood and adolescence, particularly vulnerable times for the emergence of mental health disorders. This period coincides with changes in cortical and striatal circuit refinement and reorganization.
Aim 3. will examine the postnatal development and refinement of this connectivity. The driving hypothesis is that the milestones of behavioral development are reflected in refinement of cortico-and amygdalo-BG network, particularly at the intersection of these circuits.

Public Health Relevance

Addiction is a major health problem that often starts at a young age. The brain reward circuit is fundamentally linked to the development of goal-directed behaviors and habits. This study focuses on uncovering the parts of the reward network that are instrumental for habit formation in adults and during development, the most active period of learning. This developmental period is also the time when there is a great deal of anatomical refinement of circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045573-22
Application #
8230612
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Rossi, Andrew
Project Start
1989-09-30
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
22
Fiscal Year
2012
Total Cost
$402,947
Indirect Cost
$113,271
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Haber, Suzanne N; Behrens, Timothy E J (2014) The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. Neuron 83:1019-39
Heilbronner, Sarah R; Haber, Suzanne N (2014) Frontal cortical and subcortical projections provide a basis for segmenting the cingulum bundle: implications for neuroimaging and psychiatric disorders. J Neurosci 34:10041-54
Averbeck, Bruno B; Lehman, Julia; Jacobson, Moriah et al. (2014) Estimates of projection overlap and zones of convergence within frontal-striatal circuits. J Neurosci 34:9497-505
Haber, Suzanne N; Heilbronner, Sarah R (2013) Translational research in OCD: circuitry and mechanisms. Neuropsychopharmacology 38:252-3
Haynes, William I A; Haber, Suzanne N (2013) The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation. J Neurosci 33:4804-14
Haber, Suzanne N; Knutson, Brian (2010) The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35:4-26
Kegeles, Lawrence S; Abi-Dargham, Anissa; Frankle, W Gordon et al. (2010) Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 67:231-9
Ding, Song-Lin; Haber, Suzanne N; Van Hoesen, Gary W (2010) Stratum radiatum of CA2 is an additional target of the perforant path in humans and monkeys. Neuroreport 21:245-9
May, Paul J; McHaffie, John G; Stanford, Terrence R et al. (2009) Tectonigral projections in the primate: a pathway for pre-attentive sensory input to midbrain dopaminergic neurons. Eur J Neurosci 29:575-87
Haber, Suzanne N; Brucker, Justin L (2009) Cognitive and limbic circuits that are affected by deep brain stimulation. Front Biosci 14:1823-34

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