Anna Y. Klintsova - US grants

The substantia nigra, pars compacta (SNc) is a structure that modulates voluntary motor control, and the death of the dopaminergic neurons in the SNc leads to many of the classic motor deficits associated with the Parkinson's disease (PD). Most conventional treatments alleviate symptoms but do not prevent the eventual death of neurons in the SNc. While fetal tissue transplant and stem cell therapy serve to replace lost cells, incomplete knowledge on dopamine neuron development within the SNc has limited the effectiveness of these treatments as most cells in the transplant fail to survive. Elucidating the factors that modulate dopamine neural development could lead to novel treatment approaches or increase the effectiveness of these replacement therapies in PD. In the rat brain, progesterone receptors (PRs) are expressed transiently in the perinatal SNc, suggesting a role for this hormone in the development of this region. Dr. Mennella proposes to characterize the temporal expression pattern of progesterone receptors in the mouse substantia nigra and determine their roles in the morphological and phenotypic development of that region. She also proposes to use PR knock-out (PRKO) mice to determine if absence of PRs during development leads to greater dopaminergic cell loss in the adult SNc, and more immature projections into the straitum, the primary recipient of SNc dopamine projections and greater motor deficits in adulthood.

ABSTRACT Fetal alcohol spectrum disorders (FASD) are estimated to affect 3-5% of the US population (1). Prenatal alcohol exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits (2, 3) that include abnormalities in executive functioning (EF) and working memory (4, 5). These abnormalities stem from orchestrated structural changes in several key brain regions including the prefrontal cortex (PFC) and hippocampus (HPC). While HPC and PFC have long been implicated in effective cognitive functioning, the role of the thalamic nucleus reuniens (Re), that controls information flow between these structures, has only recently been appreciated. The Re serves as a functional bridge between PFC and the HPC which are crucial for EF (6-9). Our preliminary data using a rat model of binge AE during the third trimester revealed persistent structural damage of Re, highly correlated to behavioral deficits consistent with fronto-hippocampal damage. The proposed research will test the hypothesis that binge AE during the third trimester produces neuronal loss as well as dendritic and synaptic reorganization in the Re and mPFC, which ultimately produces dysfunctional connectivity among mPFC-Re-HPC circuitry that is associated with EF deficits. In addition, we will evaluate if mPFC-Re-HPC dysfunction is mitigated via a therapeutic strategy, wheel-running (WR) followed by environmental complexity (EC), which has been successful in alleviating the deleterious AE effects on other behaviors disrupted in FASD(10-14) .Using our combined expertise in experience- dependent brain plasticity, developmental alcohol exposure and in vivo electrophysiology in freely moving rats during memory tasks, we aim to reveal AE vulnerability of the PFC-Re-HPC circuit and determine the cellular components and factors involved in plasticity of this circuit. integrity of the Re and PFC in a binge third trimester Aim 1 will establish the contributions of alcohol dose on structural AE rat model. Aim 2 working spatial memory deficits. Connectivity-behavior relationships will be will test the hypothesis that AE induces determined within the same animals via virus labeling to test the hypothesis that AE disrupts the structural connectivity between the Re, HPC and PFC. In addition, we will test the prediction that behavioral intervention (WR/EC) reduces AE-related deficits in behaviors that are dependent on the integrity of the PFC-Re-HPC circuit by enhancing neuroplasticity. We will assess whether neuroplasticity is critically dependent on increased expression of neurotrophic factors in the structural components of the circuitry. Finally, Aim 3 will determine whether AE-induced Re damage leads to reduced oscillatory synchrony between the dorsal HPC and PFC during a spatial working memory task and if WR/EC can reinstate mPFC-HPC synchrony. and in vivo Significance and Innovation : The proposed research is innovative. It will use viral neural circuit mapping multisite recording to fill a critical gap in our understanding of the mechanisms through which AE alters mPFC-Re-HPC circuitry and thus leads to cognitive impairment. Furthermore, because EF deficits are observed in children with FASD, these aims will elucidate the crucial role of mPFC-Re-HPC circuitry in the constellation of FASD deficits; thus this network may be a critical therapeutic target in FASD treatment.

ABSTRACT Fetal alcohol spectrum disorder (FASD) is estimated to affect 3-5% of the population in the United States [1]. Prenatal alcohol exposure (AE) leads to significant perturbations of brain circuitry and persisting cognitive deficits [2, 3]. The cognitive impairments associated with FASD include abnormalities in executive functioning (EF) and working memory[4, 5]. These abnormalities stem from orchestrated structural changes in several key brain regions including medial prefrontal cortex (mPFC) and hippocampus (HPC). While HPC and mPFC have long been implicated in effective cognitive functioning, the critical role of the thalamic nucleus reuniens (RE), that controls infromation flow between these structures has only recently been appreciated. Our preliminary data have revealed that prenatal AE affects the structure of RE and leads to behavioral deficits in fronto-hippocampal functitoning. The proposed research will test an innovative and novel hypothesis that developmental AE disrupts the HPC-RE-mPFC circuitry by altering the integrity of the midline thalamic RE . In healthy animals RE is reciprocally connected with the HPC and the mPFC and has been shown to be critical for a variety of working memory tasks. It is noted that while mPFC does not send direct projections to HPC, it connects with HPC via RE. Our preliminary data using animal model of binge drinking during third trimester indicate that postnatal day (PD) 4-9 AE produces persistent structural damage and loss of cells in RE in adult rat that is expected to produce a disruption in the functional connections between the three regions: mPFC, HPC and RE. The proposed research will test the hypothesis thatbinge AE during third trimester produces neuronal loss in the RE and this leads to dendritic and synaptic reorganization in thalamic RE, which ultimately produces dysfunctional connectivity with prefrontal cortex and hippocampus. Further, we will determine whether binge AE targets this nucleus exclusively and specifically among the midline thalamic nuclei and whether it affects behavior that depends on integrity of HPC-RE-PFC circuitry.In Aim 1, we will use classic and state of the art viral tracing and phenotypic analysis to reveal the effect of postnatal binge AE on neuronal organization and connectivity of RE with mPFC and HPC. Furthermore, in Aim 2 we use a specific set of behavioral assays that will reveal whether loss of HPC-RE-mPFC connectivity is critical to behavioral maladaption observed in AE. Significance and Innovation: The proposed research is innovative because it will use current viral neural circuit mapping and will fill a critical gap in our understanding of the mechanisms through which fetal alcohol exposure influence HPC-RE-mPFC circuitry damage and cognitive impairment. Further, because executive functioning deficits are observed in children with FASD, these aims will elucidate the crucial role of HPC-RE-mPFC circuitry in constellation of behavioral deficits in FASD; thus this region may be a critical therapeutic target in the treatment of FASD.