The proposal aims to identify the neural substrates in the primate brain that are responsible for abnormal socio-emotional behavior. This understanding is vital for developing both diagnostic and therapeutic approaches to identify and treat the abnormal brain circuitry in neuropsychiatric conditions such as affective and anxiety disorders. The field of social behavior research still lacks appropriate animal models for social pathology that leads to inappropriate aggression, social anxiety/phobias, social withdrawal/detachment, impulsivity, or defensiveness. The study of the neurobiology of social behavior in the nonhuman primate is especially promising since the impairment in social interactions and emotional processing generates symptomatology that resembles psychopathology observed in human patients. The proposed research seeks to investigate the novel components of the amygdala-based network that regulate socioemotional responses in nonhuman primates in order to account for imbalances that can give rise to psychopathology in the absence of structural lesions. We have determined that reversible pharmacological manipulations of specific sites within the amygdala result in profound changes in social interactions and emotional behavior in macaque monkeys. Further, we have discovered that the activation of the intermediate and deep layers of the superior colliculus (DLSC;a midbrain structure) by focal infusions of GABAA antagonist bicuculline, has a profound impact on emotional reactivity and defensive responses. In the proposed experiments, we will use the method of intracerebral focal drug infusions of either the GABA agonist muscimol or the GABA antagonist bicuculline aimed at various sites within either amygdala or DLSC to test further the role of these structures in socioemotional behavior.
Specific Aim 1 will define specific nuclei within the amygdala responsible for GABA- mediated regulation of socioemotional responses.
Aim 2 will test the hypothesis that disinhibition of DLSC will evoke aggressive behavior and emotional hyperactivity.
Aim 3 will assess the role of DLSC and amygdala in fear-potentiated startle, a conditioning paradigm that is altered in human patients with PTSD. Social interactions will be assessed in dyads, each infused animal will be paired with a familiar non-infused partner;videotaped behaviors will be analyzed by two independent observers using a standardized behavioral categorization. Special attention will be paid to reciprocal social interactions, aggressive behavior, and emergence of any abnormal behaviors (e.g., stereotypies, self-directed behaviors). Emotional reactivity will be tested by presenting the animals with a standard set of stimuli (neutral, positive, and negative). An understanding of the functional relationship between the amygdala-derived and colliculus-derived regulation of social interactions and emotional tone is expected to reveal novel targets for both etiology and therapeutic intervention for affective and anxiety disorders.
Posttraumatic stress disorder (PTSD) is an anxiety disorder resulting from exposure to a traumatic event. One of the major triggers of PTSD is combat experience and thus PTSD is particularly debilitating for military personnel and their families. Combat-related PTSD is especially debilitating because of its pervasive and long- lasting nature, and the fact that it is frequently resistant to current therapies. The goal of this proposa is to identify the neural substrates and circuitry underlying socioemotional behavior in animal models and to investigate novel sites within the neural circuits that are responsible for emergence of emotional dysregulation resembling that in combat-related PTSD. This understanding is vital for developing effective therapies for PTSD, especially in circumstances in which PTSD is long-lasting and refractory to therapeutic interventions.
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|Aguilar, Brittany L; Forcelli, Patrick A; Malkova, Ludise (2018) Inhibition of the substantia nigra pars reticulata produces divergent effects on sensorimotor gating in rats and monkeys. Sci Rep 8:9369|
|Forcelli, Patrick A; Wellman, Laurie L; Malkova, Ludise (2017) Blockade of glutamatergic transmission in the primate basolateral amygdala suppresses active behavior without altering social interaction. Behav Neurosci 131:192-200|
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|Wellman, Laurie L; Forcelli, Patrick A; Aguilar, Brittany L et al. (2016) Bidirectional Control of Social Behavior by Activity within Basolateral and Central Amygdala of Primates. J Neurosci 36:8746-56|