Studying the pathophysiology of late stage Parkinson’s disease (PD) – after the patients have experienced severe neuronal loss – has helped develop various symptomatic treatments for PD (e.g., deep brain stimulation). However, it has been of limited use in developing neuroprotective disease-modifying therapies (DMTs), because DMTs require interventions at much earlier stages of PD when vulnerable neurons are still intact. Because PD patients exhibit various non-motor prodromal symptoms (ie, symptoms that predate diagnosis), understanding the pathophysiology underlying these symptom could lead to earlier diagnosis and intervention. In my talk, I will present a recently elucidated example of how PD pathologies alter the channel biophysics of intact vagal motoneurons (known to be selectively vulnerable in PD) to drive dysautonomia that is reminiscent of prodromal PD. I will discuss how elucidating the pathophysiology of prodromal symptoms can lead to earlier diagnosis through the development of physiological biomarkers for PD.

During sexual behavior, copulation related sensory information and modulatory signals from the brain must be integrated and converted into the motor and secretory outputs that characterize ejaculation (Lenschow and Lima, Current Opinion in Neurobiology, 2020). Studies in humans and rats suggest the existence of interneurons in the lumbar spinal cord that mediates that step: the spinal ejaculation generator (SEG). My work aimed at gaining mechanistic insights about the neuronal circuits controlling ejaculation thereby applying cutting-edge techniques. More specifically, we mapped anatomically and functionally the spinal circuit for ejaculation starting from the main muscle being involved in sperm expulsion: the bulbospongiosus muscle (BSM). Combining viral tracing strategies with electrophysiology, we specifically show that the BSM motoneurons receive direct synaptic input from a group of interneurons located in between lumbar segment 2 and 3 and expressing the peptide galanin. Electrically and optogenetically activating the galanin positive cells (the SEG) lead to the activation of the motoneurons innervating the BSM and the muscle itself. Finally, inhibition of SEG cells using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in sexual behaving animals is currently conducted to reveal whether ejaculation can be prevented.

One of the best established recurrent inhibitory pathways is the recurrent inhibition of mammalian motoneurons through Renshaw cells. Golgi cells form an inhibitory feedback circuit in the granular layer of cerebellum. Feedback inhibitory pathways are long established “textbook” elements of neural circuitry, but in both cases their functional role has not been well established. Here I will present some new observations on the function of recurrent inhibition in the spinal-cord, supporting the idea that this connection frequency tunes transmission of inputs through motoneurons. Secondly, I will discuss evidence that the function of Golgi cells is much more complex than classical studies based on circuit connectivity suggest.

The vIRt nucleus in the medulla, composed of mainly inhibitory neurons, is necessary for whisking rhythm generation. It innervates motoneurons in the facial nucleus (FN) that project to intrinsic vibrissa muscles. The nearby pre-Bötzinger complex (pBötC), which generates inhalation, sends inhibitory inputs to the vIRt nucleus which contribute to the synchronization of vIRt neurons. Lower-amplitude periodic whisking, however, can occur after decay of the pBötC signal. To explain how vIRt network generates these “intervening” whisks by bursting in synchrony, and how pBötC input induces strong whisks, we construct and analyze a conductance-based (CB) model of the vIRt circuit composed of hypothetical two groups, vIRtr and vIRtp, of bursting inhibitory neurons with spike-frequency adaptation currents and constant external inputs. The CB model is reduced to a rate model to enable analytical treatment. We find, analytically and computationally, that without pBötC input, periodic bursting states occur within a certain ranges of network connectivities. Whisk amplitudes increase with the level constant external input to the vIRT. With pBötC inhibition intact, the amplitude of the first whisk in a breathing cycle is larger than the intervening whisks for large pBötC input and small inhibitory coupling between the vIRT sub-populations. The pBötC input advances the next whisk and shortens its amplitude if it arrives at the beginning of the whisking cycle generated by the vIRT, and delays the next whisks if it arrives at the end of that cycle. Our theory provides a mechanism for whisking generation and reveals how whisking frequency and amplitude are controlled.