Symptoms of many psychiatric disorders are exacerbated by stressful life events. The amygdala, which signals the presence of emotionally aversive stimuli and is dysregulated in many psychiatric disorders, has massive outputs to two key nodes of the 'stress circuit': the bed nucleus of the stria terminalis (BNST) and the central amygdaloid nucleus (CeN). Our previous work shows that the BNST and CeN have direct access to the midbrain dopamine system, which is also dysregulated by repeated stress. In this proposal we will use a monkey model to 1) examine the scope and organization of afferent inputs to specific subdivisions of the BNST and CeN, and 2) determine how information channeled through these two key nodes of the stress circuit are positioned to afferently regulate specific DA neurons and their output paths. Heightened stress reactivity is proposed to be a major risk factor for a broad range of mental illnesses, yet little is known of the organization of stress circuitry in primate models. The BNST and CeN form the rostral and caudal poles, respectively, of the central 'extended amygdala', which has been conceptualized as a unified macrostructure involved in responses to stressful stimuli. In rats, specific subdivisions of the BNST and CeN have differential responses to chronic stress, antidepressants, alcohol, and to drugs of abuse, suggesting subdivision-specific input/output paths. Despite the apparent 'symmetrical'organization of the BNST and CeN, dissociations in BNST and CeN responses to various types of stimuli suggest fundamental connectional differences. Our preliminary data in nonhuman primate indicate that while some brain regions send inputs to both BNST and CeN, other afferent systems selectively target only the BNST. This organization suggests that the BNST and CeN play related but separate roles in stress responses, and that there are fundamental differences from the rat model. The DA system is activated by novel and stressful stimuli. Since even mild stress has a significant impact on DA efflux in mesolimbic and mesocortical targets, connections between the BNST and CeN is one direct way aversive stimuli can afferently regulate this system. Our previous studies show that the DA neurons receive input from the BNST and CeN. Here, we propose to 1) more directly examine whether there is a differential afferent influence of the amygdala, hippocampus, and cortex on the BNST and CeN (Aims 1 and 2), and 2) examine how open loop systems from specific amygdaloid nuclei are channeled through BNST and/or CeN subregions to target specific DA neuron/output paths in the same animal (Aim 3).

Public Health Relevance

Stressful life events are channeled through brain regions that regulate motivated behaviors through transmitters such as dopamine. We will examine how brain regions involved in cognition influence stress circuits, as well as specific ways that stress-related information can influence motivated behavior through the dopamine system.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
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Simmons, Janine M
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University of Rochester
School of Medicine & Dentistry
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Kelly, E A; Fudge, J L (2018) The neuroanatomic complexity of the CRF and DA systems and their interface: What we still don't know. Neurosci Biobehav Rev 90:247-259
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Fudge, Julie L; Kelly, Emily A; Pal, Ria et al. (2017) Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate. Neuropsychopharmacology 42:1563-1576
Kalin, Ned H; Fox, Andrew S; Kovner, Rothem et al. (2016) Overexpressing Corticotropin-Releasing Factor in the Primate Amygdala Increases Anxious Temperament and Alters Its Neural Circuit. Biol Psychiatry 80:345-55
Torrisi, Salvatore; O'Connell, Katherine; Davis, Andrew et al. (2015) Resting state connectivity of the bed nucleus of the stria terminalis at ultra-high field. Hum Brain Mapp 36:4076-88
deCampo, Danielle M; Fudge, Julie L (2013) Amygdala projections to the lateral bed nucleus of the stria terminalis in the macaque: comparison with ventral striatal afferents. J Comp Neurol 521:3191-216
Cho, Youngsun T; Ernst, Monique; Fudge, Julie L (2013) Cortico-amygdala-striatal circuits are organized as hierarchical subsystems through the primate amygdala. J Neurosci 33:14017-30
deCampo, Danielle M; Fudge, Julie L (2012) Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area of the primate amygdala. Neurosci Biobehav Rev 36:520-35
Fudge, J L; deCampo, D M; Becoats, K T (2012) Revisiting the hippocampal-amygdala pathway in primates: association with immature-appearing neurons. Neuroscience 212:104-19
Cho, Y T; Fudge, J L (2010) Heterogeneous dopamine populations project to specific subregions of the primate amygdala. Neuroscience 165:1501-18

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