Paul M. Forlano - US grants

[unreadable] DESCRIPTION (provided by applicant): The neural circuitry of reward is an evolutionary conserved and adaptive mechanism which functions to reinforce the acquisition of essential resources, such as food and mates for species survival. Drugs of abuse hijack these same neural pathways, and continued use leads to addiction, the detriment of health and life quality, and in some cases, a permanent change in brain structures. Ample evidence exists for females to become addicted more quickly and have a greater propensity for relapse than males to drugs of abuse. However, no studies have addressed if pre-existing sexual dimorphisms exist in the structure of circuits underlying this behavior. The goal of this research is to investigate a potential neuroanatomical substrate for sex differences in addiction-related behaviors. I will quantify synaptic and neurochemical characteristics in the nucleus accumbens (NAc), an integral link in the neural circuitry of reward and addiction. My hypothesis is that NAc neurons in females not only receive greater excitatory input than males but also contain greater numbers of dopaminergic contacts in relation to excitatory inputs that may facilitate the action of dopamine during drug exposure. I will test this hypothesis by using light and electron microscopy to quantify numbers of excitatory synapses, glutamatergic input, and dopamine-positive varicosities containing or contacting excitatory synapses in male and female adult rats. While the major brain areas involved in drug addiction are well characterized, few studies have addressed why women are more prone to addiction than men. This research will provide new insights about the neural basis for sex differences in addictive behaviors. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Catecholamine systems, which include dopamine and noradrenaline, are fundamental to the processes of social incentive and reward, but relevant studies have focused almost exclusively on the mesolimbic dopamine system, which influences behavioral responses to highly processed representations of environmental stimuli However, catecholamine projections are also observed to sensory areas of the brainstem and even to the auditory periphery, suggesting that social incentive processes may begin with the modulation of responsiveness in the auditory periphery and primary sensory areas of the brain. Most studies that have investigated steroid regulation of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, have focused on long term effects of estrogen replacement on the mesocorticolimbic dopaminergic system, but not in primary sensory processing areas. The objective of this proposal is to discover how steroid hormones interact with catecholamines in circuits important for normal auditory-driven social behavioral interactions. By employing a simple but powerful vertebrate model system in a robust behavioral experiment that involves an unambiguous response to a social auditory stimulus, the activation of specific brain nuclei with homologous neurochemical contents and connections to mammals and humans will be analyzed. Furthermore, by experimental manipulation of circulating steroid hormones, a better understanding will be gained of how steroids, such as estrogen, regulate catecholamines within peripheral, primary and secondary auditory processing centers. The contribution of the proposed research is expected to provide a greater understanding of the involvement of catecholaminergic neurons during behavioral response to social auditory signals, and the mechanisms of chronic and acute steroid regulation of catecholamines in the central and peripheral auditory system. This contribution will be significant because it will become the foundation for future research that will provide insight to the role of catecholamines and their regulation by steroids in brain circuits required for normal social function. The proposed project is innovative, in our opinion, because it employs a simple vertebrate model system and has the advantage of measuring an unambiguous behavioral response to an important social auditory stimulus that is not tenable in mammalian models. PUBLIC HEALTH RELEVANCE: These findings will help delineate important, highly conserved neurochemicals, and their regulation by steroid hormones, in brain circuitry necessary for proper auditory-driven social function. This may be especially relevant to human disorders such as Asperger's syndrome and autism, which are characterized by poor orientation to social vocalizations.

The ability to locate the source of sounds enables animals to detect prey, avoid predators and communicate with others and is thus basic to survival in many species. While decades of behavioral, physiological and neuroanatomical research have revealed the physical cues and neural mechanisms that terrestrial animals use to localize sound, the mechanisms used by fish, the oldest living vertebrate group, remain a mystery. Collectively, these experiments will investigate the mechanisms of sound localization utilized by fish that likely formed the evolutionary foundation for more recent modes of vertebrate hearing and sound localization. Throughout the project, Drs. Sisneros and Forlano will train and mentor both graduate and undergraduate students and give annual public lectures regarding the supported research at the Friday Harbor Labs (FHL). As an integral part of this research program, Drs. Sisneros and Forlano will host GK-12 teachers every summer at FHL where they will participate in field and laboratory experiments. The researchers will also develop lesson plans, student projects and an educational website with the teachers at their home institutions.

The investigation will take an integrated behavioral, anatomical, and brain activational approach to determine whether fish are fundamentally similar to other studied vertebrates, and use binaural information (information from both ears) to localize sound, or are fundamentally different, and achieve robust localization on the basis of monaural (single-ear) information alone. The central hypothesis to be tested is that binaural integration is essential for sound source localization in midshipman. To test this hypothesis, the investigators will 1) determine which inner ear endorgans are required for sound localization behavior by testing animals in an established sound playback paradigm before and after systematic unilateral or bilateral removal of each endorgan's otolith (saccule, lagena, utricle), 2) characterize the ipsilateral and contralateral projections of inner ear afferents from all three endorgans to known auditory processing regions in the hindbrain by bulk labeling each endorgan separately or in double or triple combination with different fluorescent-labeled dextran amine tracers, and 3) characterize the brain activation patterns resulting from controlled auditory directional stimulation in intact animals and in those that have undergone systematic endorgan removal, using c-Fos as a marker for neural activation. Duplicate digital files of all raw, processed and consolidated data will be stored locally and in the cloud by both researchers and will be made publically available within two years following publication.

Training a diverse neuroscience workforce to address health disparities is critical when considering the cost and burden on society of unequal care and treatment among racial and ethnic groups. Numerous reports link socioeconomic and ethnic disparities to the frequency, care, and severity of brain disorders and disabilities including stroke, neurodegenerative disease, epilepsy, addiction, traumatic brain injury, and psychological disorders. The Borough of Brooklyn has a population of over 2.6 million, one of the most diverse urban communities in the nation. Brooklyn College (BC) of City University of New York (CUNY), State University of New York Downstate Medical Center (Downstate), and Medgar Evers College (MEC) of CUNY are located within a few miles of each other in a part of Brooklyn that is overwhelmingly populated by under-represented groups: 50% of the population is comprised of Black residents primarily from West Indian and Afro-Caribbean backgrounds, and 12% is Hispanic, also of Caribbean origins. Our institutions will partner to develop a neuroscience-focused educational and research agenda ranging from basic neural processes to cognitive and behavioral neuroscience, including the introduction of Fellows to the socioeconomics of health disparities and public health issues related to neurological health and disease in minority communities. Our program, BP- ENDURE: Brooklyn Neural NETS (Neuroscience Education and Training for Scientists) or B-NETS, is intended to prepare well-qualified underrepresented (UR) juniors and seniors who are interested in careers in the neurosciences requiring PhD or MD/PhD degrees. Such individuals will both increase the diversity of researchers in neuroscience and contribute research findings that can help to address chronic neurological conditions that occur more frequently in minority and low-income populations, including the catchment area of the participating institutions where our students live and study. Working as a tightly knit consortium and exploiting prior successful cross-institution collaborations, B-NETS will have the experience, scientific expertise, assessed institutional need, and motivation to develop a highly effective BP-ENDURE program for upper division undergraduate students from UR backgrounds. The proposed B-NETS program will meet the goal of developing neuroscience research education programs by creating a full neuroscience major at BC and an expanded neuroscience curriculum at MEC. The senior administration of all three B-NETS partner institutions has prioritized STEM diversity programs and increasing faculty diversity and fully supports the B- NETS program. Many of our UR undergraduates, including some in programs like MARC and RISE, express the goal of becoming college faculty and serving as research mentors for UR undergraduates like themselves ? a vital pipeline to increase the size of the pool of UR faculty. Innovative aspects of the B-NETS program include the blending of basic neuroscience, behavioral neuroscience, community-engaged research and an outstanding depth in neuroscience research to develop a new cohort of diverse neuroscience researchers.