Biology subjects

Essig, J.

Publications and source records attributed to Essig, J..

3 recordsLinked to original sources

bioRxiv2026

PV interneuron-targeted CRISPRa rescue of SCN1A haploinsufficiency in Dravet syndrome

Dravet syndrome is a severe epileptic encephalopathy caused by SCN1A haploinsufficiency, which leads to reduced NaV1.1 expression in parvalbumin (PV)-expressing interneurons and disrupted excitatory-inhibitory balance in the brain. We developed an AAV-based CRISPR activation system (AAV9-E2-dCas9-VP64) to selectively upregulate SCN1A from its endogenous locus in PV interneurons. An in vitro saturating guide RNA (gRNA) screen across the human SCN1A promoter identified a lead guide with robust and highly specific engagement of the SCN1A locus. This lead gRNA was validated in human Dravet syndrome model GABAergic neurons, where dose-dependent and specific SCN1A upregulation was observed. Intracerebroventricular (ICV) administration in a mouse model of Dravet syndrome produced dose-dependent improvement in survival as well as reduced susceptibility to hyperthermia-induced seizures and increased NaV1.1 protein expression, with maintained PV interneuron selectivity and minimal off-target expression. In a study in juvenile cynomolgus macaques, MRI-guided ICV administration of the vector was well tolerated, achieved broad cortical biodistribution, and maintained strong detargeting of peripheral tissues, with substantially lower peripheral dCas9 expression relative to the brain. These results support PV interneuron-selective SCN1A gene modulation via CRISPR activation as a promising therapeutic strategy for Dravet syndrome. AAV9-E2-dCas9-VP64 (RT101) is currently in preclinical development and is being advanced toward evaluation in the clinic.

neuroscience↗

bioRxiv2021

Functional coupling between target selection and acquisition in the superior colliculus

To survive in unpredictable environments, animals must continuously evaluate their surroundings for behavioral targets, such as food and shelter, and direct their movements to acquire those targets. Although the ability to accurately select and acquire spatial targets depends on a shared network of brain regions, how these processes are linked by neural circuits remains unknown. The superior colliculus (SC) mediates the selection of spatial targets and remains active during orienting movements to acquire targets, which suggests the underexamined possibility that common SC circuits underlie both selection and acquisition processes. Here, we test the hypothesis that SC functional circuitry couples target selection and acquisition using a default motor plan generated by selection-related neuronal activity. Single-unit recordings from intermediate and deep layer SC neurons in male mice performing a spatial choice task demonstrated that choice-predictive neurons, including optogenetically identified GABAergic SC neurons whose activity was causally related to target selection, exhibit increased activity during movement to the target. By strategically recording from both rostral and caudal SC neurons, we also revealed an overall caudal-to-rostral shift in activity as targets were acquired. Finally, we used an attractor model to examine how target selection activity in the SC could generate a rostral shift in activity during target acquisition using only intrinsic SC circuitry. Overall, our results suggest a functional coupling between SC circuits that underlie target selection and acquisition, elucidating a key mechanism for goal-directed behavior. Significance StatementThe ability to quickly select and acquire spatial targets is essential to animal survival. Neural circuits underlying these processes are shared in an interconnected network of brain regions, however it is unclear how circuits link decision-making processes with motor commands to execute choices. Here, we examine single-unit activity in the superior colliculus (SC) as mice select and acquire spatial targets to test the hypothesis that choice-related activity promotes target acquisition by generating a default motor plan for orienting movements. By demonstrating that choice-predictive neurons increase their firing rates during movement and capturing the dynamics of SC activity with an attractor model of intrinsic SC circuitry, our results support a role for SC circuits in coupling target selection and acquisition.

neuroscience↗

bioRxiv2020

Inhibitory midbrain neurons mediate decision making

Decision making is critical for survival but its neural basis is unclear. Here we examine how functional neural circuitry in the output layers of the midbrain superior colliculus (SC) mediates spatial choice, an SC-dependent tractable form of decision making. We focus on the role of inhibitory SC neurons, using optogenetics to record and manipulate their activity in behaving mice. Based on data from SC slice experiments and on a canonical role of inhibitory neurons in cortical microcircuits, we hypothesized that inhibitory SC neurons locally inhibit premotor output neurons that represent contralateral targets. However, our experimental results refuted this hypothesis. An attractor model revealed that our results were instead consistent with inhibitory neurons providing long-range inhibition between the two SCs, and terminal activation experiments supported this architecture. Our study provides mechanistic evidence for competitive inhibition between populations representing discrete choices, a common motif in theoretical models of decision making.

neuroscience↗