Animal survival depends on the brain’s ability to detect the energetic state of the body and to alter behaviour in order to maintain homeostasis. Current research in the control of food consumption stresses the importance of identifying and establishing the specific roles of homeostatic neurons, which sense the body’s energetic state and elicit complex and flexible food seeking behaviours. Recent developments in optogenetics, molecular genetics, and anatomical techniques have made these investigations possible at the resolution of specific cell types and circuits. These neurons are of particular interest because they serve as key entry points to the identification of downstream circuits and reinforcement mechanisms that control feeding behaviour. This dissertation probes the role of two kinds of homeostatic neurons— agouti-related peptide (AGRP) in the arcuate nucleus (ARC) and leptin receptor (LepRb) neurons in the lateral hypothalamic area (LHA)—in the control of food intake. First, I examined the role of LepRb neurons in the LHA in feeding. Results from electrophysiological studies indicate that these neurons consist of a subpopulation of homeostatic sensing LHA γ-aminobutyric acid (GABA) expressing neurons. In addition to their response to leptin, these neurons are capable of modulating their activity in response to changes in glucose levels, further substantiating their role as homeostatic sensing neurons. Behavioural studies using optogenetic activation of these neurons show that their elevated activity is capable of reducing body weight, although their role in modulating feeding remains unclear. Second, I investigated the reinforcement mechanisms employed by AGRP neurons to elicit voracious food consumption and increased willingness to work for food. Conditioned place avoidance studies under optogenetic activation of AGRP neurons reveal that their increased activity has negative valence and is avoided. In addition, imposition of elevated AGRP neuron activity in an operant task reduced instrumental food seeking with particular sensitivity under high effort requirements. Taken together, these results suggest that AGRP neurons employ a negative reinforcement teaching signal to direct action selection during food seeking and consumption. Third, I systematically analyzed the contribution of specific AGRP neuron projection subpopulations in AGRP neuron mediated evoked-feeding behaviour. Optogenetic activation studies of AGRP neuron axons in downstream projection regions indicate that several, but not all, subpopulations are capable of independently evoke food consumption. This work reveals a parallel and redundant functional circuit organization for AGRP neurons in the control of food intake. Interestingly, all AGRP neuron subpopulations examined displayed similar modulation by states of energy deficit and signals of starvation, despite their apparent divergence in function. As a whole, this dissertation extends our understanding of the role of homeostatic neurons in food consumption and uncovers previously unappreciated functional organization and reinforcement mechanisms employed by neuronal circuits that control feeding behaviour.

No / The chemical and biological nonproliferation regime stands at a watershed moment, when failure seems a real possibility. After the unsuccessful outcome of the 2016 Eighth Review Conference, the future of the Biological and Toxin Weapons Convention is uncertain. As the Chemical Weapons Convention (CWC) approaches its Fourth Review Conference in 2018, it has almost completed removing the huge stocks of chemical weapons, but it now faces the difficult organizational task of moving its focus to preventing the reemergence of chemical weapons at a time when the international security situation appears to be increasingly more difficult and dangerous. In this article, we assess the current and near-term state (5–10 years) and impact of three related areas of science and technology that could be of dual-use concern: targeted delivery of agents to the central nervous system (CNS), particularly by means of nanotechnology; direct impact of nanomaterials on synaptic functions in the CNS; and neuronal circuits in the brain that might be targeted by those with hostile intent. We attempt to assess the implications of our findings, particularly for the consideration of the problem of state-level interest in so-called nonlethal incapacitating chemical agents for law enforcement at the CWC Review Conference in 2018, but also more generally for the longer-term future of the chemical and biological nonproliferation regime.

Protocadherins (Pcdhs) are a large family of adhesion molecules which have structure similar to that of classical cadherins. About 60 Pcdh genes are organized into three clusters (-á,- â and- ã), which are arranged contiguously on a single chromosome in mammals. Mice in which the 22-gene Pcdh- ã locus has been deleted die within a few hours of birth and show defects in movement and reflexes, extensive neurodegeneration in the spinal cord, and loss of synapses. Further studies have shown that loss of ã-Pcdhs has a primary effect on the formation or maintenance of synapses that can be dissociated from its role in cell survival. Extensive apoptotic cell death observed during the late embryonic development period in the spinal cord of the Pcdh- ã del/del mutant mice is confined to molecularly distinct populations of spinal interneurons. Analysis of cell death patterns during development of spinal cords from wild-type, the Pcdh- ã del/del and Bax -/- mice in which cell death is blocked due to deletion of a proapoptotic protein, confirmed that loss of ã-Pcdhs exacerbates a previously undocumented normal developmental pattern of spinal interneuron apoptosis. Restricted disruption of the Pcdh- ã gene cluster within specific neuronal populations suggested that ã-Pcdhs can control neuronal survival in a non-cell autonomous manner. Loss of ã-Pcdhs also resulted in an aberrant pattern of 1a proprioceptive sensory afferent (1aPSA) terminals in the spinal cord. In Pcdh- ã del/del mice the area occupied by 1aPSA terminals per motor neuron increased by 150% over the control with a corresponding reduction of 30% in the area occupied by 1aPSA terminals on the ventral interneurons. Further analysis in the Pcdh- ã del/del; Bax-/- double mutants, as well as in mouse lines in which Pcdh- ã gene cluster disruption was confined to specific neuronal subpopulations, suggested that this aberrant pattern was a result of both the increased loss of ventral interneurons in mutants, as well as a cell autonomous requirement of ã-Pcdhs in the 1aPSA and their intermediate target ventral interneurons. These studies provide evidence that the ã-Pcdhs mediate homophilic interactions that are important for the formation of multiple neuronal circuits, and are critical molecules in the regulation of interneuron survival and CNS development.

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