Forming functional cell groups in the developing brain

The complexity of the adult brain originates from a simple developmental structure called the neural tube. There are a number of cellular developmental processes that occur in an orchestrated fashion to mediate the transition from neural tube to adult brain. These include processes such as cell division, migration, and specification, process outgrowth, and path finding, in addition to programmed or signal induced cell death (often apoptosis). These processes are usually dependent on a combination of internal programming and external cues. While the formation of layered structures such as seen in the cortex has been well studied (1), the formation of nuclear cell groups in the hypothalamus is less understood. Hypothalamic nuclear groups are heterogeneous populations of cells that regulate the autonomic nervous system, motivated behavior and endocrine balance. Neurons in the paraventricular nucleus (PVN) of the hypothalamus, for example, control body temperature and metabolism via thyrotropin releasing-hormone containing cells, blood pressure via vasopressin containing cells, stress responses via corticotropin releasing hormone and vasopressin containing cells, reproductive function via oxytocin containing cells. The PVN also integrates information from other brain regions and samples hormone and emotional status to determine appropriate output/activity of its various cell types (2). From a developmental perspective the molecular specificity needed to direct cells to the correct location, initiate correct gene expression and connect to the appropriate circuits presents a difficult problem to solve. It has been hypothesized that small interferences (genetic or environmental) to this process cause changes in cytoarchitecture that impact adult physiology and contribute to pathology (3). A limited number of signaling pathways thought important for the development of hypothalamic cell groupings have been identified. GABA B receptor signaling may play important roles in formation of the PVN. For one, components of the pathway are expressed in a spatiotemporal pattern suggesting it could be important for PVN development (4). Secondly, dysregulation of GABA B signaling pathways or genetic mutation of components in the pathway have been associated with disorders resulting from altered PVN function (5, 6). Previous studies have shown that when the GABA B signaling pathway is disrupted, cytoarchitecture and peptide expression in the PVN is altered (4, 7). In this pilot study mice were embryonically exposed to the GABA B receptor antagonist 2-hydroxy-saclofen and adult anxiety like behaviors and depressive like behaviors were assayed using the elevated plus maze (8) and forced swim (9) test, respectively. Preliminary data suggests that embryonic saclofen exposure caused increased depressive like behaviors as indicated by increased floating time in the forced swim test. We suggest that developmental disruption of GABA B receptor signaling can cause changes in cyto-architecture that may alter adult physiology and behavior.