Survival depends on the selection of behaviors adaptive for the current environment. For example, a mouse should run from a rapidly looming hawk but should freeze if the hawk is coasting across the sky. Although serotonin has been implicated in adaptive behavior, environmental regulation of its functional role remains poorly understood. We found that stimulation of dorsal raphe serotonin neurons suppressed movement in low- and moderate-threat environments but induced escape behavior in high-threat environments, and that movement-related dorsal raphe serotonin neural dynamics inverted in high-threat environments. Stimulation of dorsal raphe GABA neurons promoted movement in negative but not positive environments, and movement-related GABA neural dynamics inverted between positive and negative environments. Thus, dorsal raphe circuits switch between distinct operational modes to promote environment-specific adaptive behaviors.

Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at subpopulations of projection neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC. We first show that D1 receptors are enriched in pyramidal cells in both layers 5 and 6, and that these cells project to intratelencephalic targets including contralateral cortex, striatum, and claustrum rather than to extratelencephalic structures. We then find that D1 receptors are also present in interneurons and enriched in superficial layer VIP-positive (VIP+) interneurons that coexpresses calretinin but absent from parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons. Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these corticocortical neurons and VIP+ interneurons. Our findings define several novel subpopulations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory microcircuits in the PFC.

Dopamine modulation in the prefrontal cortex (PFC) mediates diverse effects on neuronal physiology and function, but the expression of dopamine receptors at sub-populations of pyramidal neurons and interneurons remains unresolved. Here, we examine D1 receptor expression and modulation at specific cell types and layers in the mouse prelimbic PFC.We first show that D1 receptors are enriched in pyramidal neurons in both layers 5 and 6, and that these cells project intra-telencephalically, rather than to sub-cortical structures.We then find that D1 receptors are also present in interneurons, and enriched in VIP+ interneurons that co-expresses calretinin, but absent from PV+ and SOM+ interneurons.Finally, we determine that D1 receptors strongly and selectively enhance action potential firing in only a subset of these cortico-cortical neurons and VIP+ interneurons. Our findings define several novel sub-populations of D1+ neurons, highlighting how modulation via D1 receptors can influence both excitatory and disinhibitory micro-circuits in the PFC. neurons that project sub-cortically (Gabbott PL et al. 2005; Dembrow NC et al. 2010; Anastasiades PG et al. 2018). Recent studies indicate that dopamine receptors may differentially segregate between these two broad populations of layer 5 projection neurons in the PFC (Gee S et al. 2012; Seong HJ and AG Carter 2012; Clarkson RL et al. 2017).Interestingly, D1-Rs are also expressed in layer 6 (L6), where they may modulate corticothalamic (CT) projections (Gaspar P et al. 1995). However, there is currently no consensus on which projection neurons primarily express D1-Rs, with reports varying significantly (Vincent SL et al. 1993;Gaspar P et al. 1995). Given that the activity of defined projection 4 neurons can have distinct effects on behavior (Land BB et al. 2014;Jenni NL et al. 2017; Murugan M et al. 2017; Otis JM et al. 2017), this represents a significant gap in our understanding of how dopamine modulates PFC outputs.Like other cortices, the PFC also contains a diverse array of GABAergic interneurons (Markram H et al. 2004; Petilla Interneuron Nomenclature G et al. 2008;Anastasiades PG and SJ Butt 2011;Rudy B et al. 2011). Interneurons are segregated into distinct subtypes based on their intrinsic electrophysiology, morphology, and immunohistochemical markers (Kubota Y and Y Kawaguchi 1994;Kawaguchi Y and Y Kubota 1996;Butt SJ et al. 2005;Gonchar Y et al. 2007;Xu X et al. 2010;Anastasiades PG et al. 2016). Moreover, dopamine receptors are thought to be expressed in several populations of interneurons (Muly EC, 3rd et al. 1998;Glausier JR et al. 2009;Santana N et al. 2009), where they can mediate diverse effects (Gonzalez-Islas C and JJ Hablitz 2001;Kroner S et al. 2007;Towers SK and S Hestrin 2008;Karunakaran S et al. 2016). However, as with projection neurons, there are conflicting reports on which interneuron subtypes express D1-Rs in the PFC (Le Moine C and P Gaspar 1998;Muly EC, 3rd et al. 1998;Paspalas CD and PS Goldman-Rakic 2005;Santana N et al. 2009). While neuromo...

Trials Conference was held, which focused on current issues related to AEDD development from preclinical models to clinical prognostication. The conference featured regulatory agencies, academic laboratories, and healthcare companies involved in emerging epilepsy therapies and research. The program included discussions around funding and support for investigations in epilepsy and neurologic research, clinical trial design and integrated outcome measures for people with epilepsy, and drug development and upcoming disease-modifying therapies. Finally, the conference included updates from the preclinical, clinical, and device pipeline. Summaries of the talks are provided in this paper, with the various pipeline therapeutics in the listed tables to be outlined in a subsequent publication.

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