Distinct Circuit States Enable State-dependent Flexibility in a Rhythm Generating Network

My thesis aimed to elucidate general organizing principles underlying the modulation of neural circuits. These circuits are flexible constructs that, when modulated, can occupy many distinct states and produce different output patterns. Distinct circuit states can also produce the same output pattern in some cases. However, understanding the mechanisms and consequences of this latter phenomenon is impossible to achieve without the capability to observe and manipulate the cellular and synaptic properties of all circuit neurons. This work takes advantage of our detailed, cellular-level access to the central pattern generator (CPG) circuits found in the decapod crustacean stomatogastric nervous system, a specialized extension of the CNS dedicated to internal feeding-related behaviors. As CPGs are rhythmically active networks, much of this work focuses on the ability of such circuits to produce rhythmic output patterns (i.e. rhythm generation). Using this system, I found that distinct circuit states (configured by MCN1 projection neuron stimulation and CabPK peptide application) can enable comparable rhythm generation by recruiting distinct ionic conductances with overlapping functional roles (i.e. IMI and ITrans-LTS), each being regulated by synaptic inhibition to produce phasic excitatory drive to a pivotal circuit neuron (LG). In one case (MCN1 stimulation), the conductance is activated by a modulatory peptide transmitter whose release is regulated by presynaptic feedback inhibition. In the other case (CabPK application), the conductance has a slow inactivation property that is removed by hyperpolarization caused by synaptic inhibition. I also describe the consequences of having different circuit states that produce identical outputs by assaying their responses to the same, well-defined modulatory inputs peptide (CCAP) hormone modulation and sensory feedback (GPR neuron). I found that hormonal modulation produced opposite effects on these two circuits states even though the cellular-level hormonal action is likely the same in both states. In contrast, I found these circuits were similarly sensitive to sensory feedback, despite this feedback acting via different synapses under each condition. My work thereby provides the first mechanistic understanding of input-pathway specific rhythm generators that produce convergent output patterns and the flexibility enabled by these circuit states when responding to additional modulatory inputs. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Neuroscience First Advisor Michael P. Nusbaum Subject Categories Neuroscience and Neurobiology This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1422 This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1422 DISTINCT CIRCUIT STATES ENABLE STATE-DEPENDENT FLEXIBILITY IN A RHYTHM GENERATING NETWORK Jason Christopher Rodriguez