Mechanisms Regulating Neuronal Survival in the Mammalian Basal Ganglia

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Background. Our program focuses on how structure and function is determined in the mammalian basal ganglia, a key network of nuclei that modulate motor coordination, cognition and limbic related behaviour. Both cell autonomous and non-autonomous factors determine the complement of adult central nervous system (CNS) neurons. Despite significant advances in understanding the cellular machinery underlying developmental cell death, less is known of how connectivity networks determine neuronal subtypes in different brain nuclei. The classic neurotrophic hypothesis proposes that neurons faced with developmental or degenerative apoptotic stress compete for limiting concentrations of target-derived growth factors. The theory derives mainly from work in the peripheral nervous system (PNS), with less work in more complex CNS systems. However, increasing evidence suggests afferent inputs are also important determinants of survival in the CNS, matching activity to the final complement of neuronal subtypes. Our overarching goal is to determine how different afferent systems modulate the survival of highly heterogeneous striatal subpopulations that correspond to specific functional motor networks. Aims. In recent work, focused on two key basal ganglia components, the ventral midbrain and striatum, we discovered that neurotransmitter systems and neurotrophins cooperate to play a crucial anterograde trophic role, matching activity with survival of specific neuronal phenotypes. We now propose that glutamatergic thalamic (TS) or cortical (CS) striatal afferents play important developmental trophic roles, with distinct survival or differentiation effects on different neuronal subtypes (Aim #1). As a mechanism, we propose anterograde trophic signaling in the TS system by the neurotrophin brain derived neurotrophic factor (BDNF) enhances survival of specific TrkB-positive targets on a background of depolarizing glutamatergic activity (Aim #2). Furthermore, we propose the complement of TS-dependent striatal neurons is functionally relevant, modulating for example the balance between hyperkinetic/facilitatory or hypokinetic/inhibitory motor behaviour. Significance. We will help discover fundamental mechanisms by which afferents promote survival of specific neurons in the developing mammalian CNS, using the striatum as a model. Afferent-mediated rescue of TrkB-positive targets on a background of depolarizing activity may be an important mechanism for specifying the appropriate complement of striatal subtypes. The striatum is especially compelling as a model since its heterogeneous subtypes modulate different aspects of motor and non-motor behaviors. Matching target composition to afferent trophic activity may therefore represent a fundamental mechanism that determines motor function. Recapitulating similar mechanisms in the adult may implicate afferents in important maintenance roles, and also provide important insight into healthy ageing and neurodegeneration.