David T. Hsu, Ph.D. - US grants

DESCRIPTION (provided by applicant): The broad, long-term goal of this proposal is to elucidate the organization of neural systems that determine mood and affect. The primary objective of the proposed research is to define in monkeys the axonal pathways by which the midbrain periaqueductal gray (PAG) may influence cortical function. The PAG as a critical component in generating emotional expression, and distinct subdivisions of the PAG coordinate distinct emotional reactions to different types of stress. The PAG projects extensively to the midline/intralaminar thalamic nuclei (ILN), which represents one likely pathway through which the PAG may influence cortical function. In rats, individual ILN project to circumscribed areas of the cerebral cortex that correspond to the primate orbital and medial prefrontal cortex (OMPFC), a cortical area thought to be involved in the highest levels of emotional processing. Although these pathways to the cerebral cortex are best known in rats, the OMPFC is much more developed and better known in monkeys. In particular, the primate OMPFC can be divided into distinct functional networks that are hypothesized to subserve different components of emotion. It is hypothesized that the ascending pathways from subdivisions of the PAG will interact differentially with the two networks, reflecting their differential role in emotional reactions to stress. A clear understanding of how this pathway is linked in primates may provide insight into the neural basis of psychiatric illnesses such as major depression and anxiety disorders, which are characterized by maladaptive emotional responses to stress.

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award will support the candidate in transitioning into an independent investigator in translational research with a focus on mood disorders. With a background in animal research, the candidate proposes training in human functional magnetic resonance imaging (fMRI) to investigate brain activity associated with social rejection and acceptance. Social rejection (an explicit declaration that an individual is not liked) has powerful effects on emotion and behavior including lowered self- esteem, major depression, risk-taking behavior, substance abuse, and violence. A few fMRI studies have found increased activity in the anterior cingulate cortex using different paradigms for social rejection. The first aim of the project is to test experimental manipulations for social rejection, explore its parameters, and adapt a stimulus presentation for use in fMRI experiments. The second aim is to use fMRI to examine neuronal pathways involved in social rejection. Based on anatomical pathways found in rats and monkeys, it is hypothesized that in addition to the anterior cingulate cortex, activation will be found in the periaqueductal gray, thalamus, amygdala, nucleus accumbens, and subgenual cortex. These structures are known to be involved in stress responses and major depression, as well as responding to rewards. An exploratory aim will assess behavioral responses to social rejection in patients with Major Depressive Disorder (MDD) without fMRI. Once the behavioral responses are studied, my long-term goal is to examine abnormal neuronal responses to social rejection in MDD with neuroimaging. Atypical depression, for example, is uniquely characterized by intense social rejection sensitivity. Identifying a unique biological profile for a depressive subtype may improve its definition, diagnosis, and treatment. PUBLIC HEALTH RELEVANCE: Social rejection can lead to major depression and social anxiety. This proposal seeks to understand how the brain processes social rejection. The results may help us to identify those who are vulnerable to the effects of social rejection, and lead to innovative treatments and preventive measures.

DESCRIPTION (provided by applicant): Humans depend on acceptance into groups and intimate relationships for survival and emotional well- being. Actual or perceived threats to this need such as social rejection (when one is not wanted or liked) can lead to marked changes in mood and behavior such as sadness, social withdrawal, and impulsivity. The experience of severe or repeated social rejection in those who are rejection sensitive is a strong contributor to psychiatric disorders such as major depressive, social anxiety, and personality disorders. The neurotransmitter mechanisms underlying rejection sensitivity (RS) are not known. It has been known for over 30 years in nonhuman animals that the endogenous opioid system, particularly the ¿-opioid receptor (MOR) system, regulates social distress and social reward behaviors. Using positron emission tomography, we recently showed that social rejection and acceptance produced robust MOR- mediated neurotransmission in specific brain areas, which correlated with changes in mood and behavior. This study was the first to show that the endogenous opioid system responds to social cues in humans. The proposed project will examine the MOR system in the clinically important trait of RS. Since the neurotransmitter mechanisms of RS are unknown, we seek to first understand the basic neurobiology of RS in a healthy population, prior to studying clinical populations. The overall hypothesis is that RS is associated with MOR function. Those with higher RS compared to lower RS are hypothesized to have overall lower MOR activation during social rejection and acceptance, leading to greater distress and dampened pro-social behavior. Numerous animal studies have also established that the MOR system is strongly influenced by harmful social environments. Therefore, we will also examine the role of childhood maltreatment (CM), a negative early life experience known to be one of the highest risk factors for developing depression and anxiety. The goal of this project is to determine how RS and CM interact to determine patterns of MOR binding during baseline, social rejection, and social acceptance in a healthy population. We will also examine how RS, mediated through MOR activation, influences mood and behavior. The impact of this research is to provide the first major step towards understanding a neurotransmitter mechanism for RS, with the long-term goal of predicting and treating its associated disorders.