Midbrain ventral tegmental neurons project to the prefrontal cortex and modulate cognitive functions. Using viral tracing, optogenetics and electrophysiology, we found that mesocortical neurons in the mouse ventrotegmental area provide fast glutamatergic excitation of GABAergic interneurons in the prefrontal cortex and inhibit prefrontal cortical pyramidal neurons in a robust and reliable manner. These mesocortical neurons were derived from a subset of dopaminergic progenitors, which were dependent on prolonged Sonic Hedgehog signaling for their induction. Loss of these progenitors resulted in the loss of the mesocortical inhibitory circuit and an increase in perseverative behavior, whereas mesolimbic and mesostriatal dopaminergic projections, as well as impulsivity and attentional function, were largely spared. Thus, we identified a previously uncharacterized mesocortical circuit contributing to perseverative behaviors and found that the diversity of dopaminergic neurons begins to be established during their progenitor phase.

The hippocampal dentate gyrus is an important relay conveying sensory information from the entorhinal cortex to the hippocampus proper. During exploration, the dentate gyrus has been proposed to act as a pattern separator. However, the dentate gyrus also shows structured activity during immobility and sleep. The properties of these activity patterns at cellular resolution, and their role in hippocampal-dependent memory processes have remained unclear. Using dual-color in-vivo two-photon Ca2+ imaging, we show that in immobile mice dentate granule cells generate sparse, synchronized activity patterns associated with entorhinal cortex activation. These population events are structured and modified by changes in the environment; and they incorporate place- and speed cells. Importantly, they are more similar than expected by chance to population patterns evoked during self-motion. Using optogenetic inhibition, we show that granule cell activity is not only required during exploration, but also during immobility in order to form dentate gyrus-dependent spatial memories.

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding, and deficits in spatial memory. Two-photon glutamate uncaging experiments revealed a marked increase in the fraction of hippocampal 1st order CA1 pyramidal cell dendrites capable of generating dendritic spikes in the kainate model of chronic epilepsy. Moreover, in epileptic mice dendritic spikes were generated with lower input synchrony inputs, and with a lower threshold. The Nav1.3/1.1 selective Na+ channel blocker ICA-121431 reversed dendritic hyperexcitability in epileptic mice, while the Nav1.2/1.6 preferring anticonvulsant S-Lic did not. We used in-vivo two-photon imaging to determine if aberrant dendritic excitability is associated with altered place-related firing of CA1 neurons. We show that ICA-121431 improves degraded hippocampal spatial representations in epileptic mice. Finally, behavioural experiments show that reversing aberrant dendritic excitability with ICA-121431 reverses hippocampal memory deficits. Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.

All vertebrates are capable of generating dissimilar patterns of neuronal activity from similar sensory-driven input patterns, a phenomenon called pattern separation. It is unclear, however, how these separated patterns are transformed into lasting memories that retain the initial discrimination. Using dual-color in-vivo two-photon Ca 2+ imaging, we show that the dentate gyrus, a region implicated in pattern separation, generates in immobile mice sparse, synchronized activity patterns driven by entorhinal cortex activity. These population events are structured and modified by changes in the environment; they incorporate place-and speed cells and are similar to population patterns evoked during self-motion. Inhibiting only granule cells in immobile mice impairs formation of pattern-separated memories. These patterns, thus, support the creation of precise memories by replaying the population codes of the current environment on a short time scale. Results Sparse, structured dentate network events in immobile animalsWe imaged the activity of >300 granule cells (GCs) using a Thy1-GCaMP6s mouse line (GP4.12Dkim/J,15 ). In addition, we monitored the activity of the major input system into the dentate gyrus, the medial perforant path (MPP). To this end, we expressed the red-shifted Ca 2+ indicator jRGECO1a 16 in the medial entorhinal cortex using viral gene transfer (see Methods section, Fig. 1A, B, Supplementary Fig. 1A). To allow efficient excitation of both genetically encoded Ca 2+ indicators, we established excitation with two pulsed laser sources at 940 and 1070 nm (see Supplementary Fig. 1B). The mice were placed under a two photon microscope and ran on a linear track (see Supplementary Fig. 1C, Supplementary Movie 1).As previously described, the firing of GCs was generally sparse 7-9,17 , both when animals were immobile and running on a textured belt without additional cues (mean event frequency 1.38±0.19 events/min and 0.97±0.2 events/min, respectively, n=9 mice, Fig. 1B, Supplementary Fig. 2C-F). Despite the sparse activity of granule cells, we observed synchronized activity patterns. To rigorously define such events, we used an algorithm that detects synchronized network events within a 200 ms time window (see Methods). Such synchronous network events could readily be observed in the dentate gyrus ( Fig. 1C, D, network events depicted in different colors, see corresponding Supplementary Movie 2).Network events were sparse, incorporating only 5.7±0.09 % of the active GC population.Notably, network events occurred mainly during immobility and were much less prevalent during running (Fig. 1D, E). Shuffling analysis (see Methods) confirmed that network events cannot arise by chance (Fig 1E, grey bars correspond to shuffled data, ANOVA F (3,25) =30.12, p=4*10 -14 , Bonferroni post-test resting vs. shuffled p=2.2*10 -10 indicated with asterisk, running vs. shuffled p=1). Simultaneous imaging of MPP and GC activity showed that network events were strongly correlated with MPP activity increases (Fig. 1F). Moreover, ...

Memory deficits are a debilitating symptom of epilepsy, but little is known about mechanisms underlying cognitive deficits. Here, we describe a Na+ channel-dependent mechanism underlying altered hippocampal dendritic integration, degraded place coding, and deficits in spatial memory.Two-photon glutamate uncaging experiments revealed that the mechanisms constraining the generation of Na+ spikes in hippocampal 1st order pyramidal cell dendrites are profoundly degraded in experimental epilepsy. This phenomenon was reversed by selectively blocking Nav1.3 sodium channels. In-vivo two-photon imaging revealed that hippocampal spatial representations were less precise in epileptic mice. Blocking Nav1.3 channels significantly improved the precision of spatial coding, and reversed hippocampal memory deficits.Thus, a dendritic channelopathy may underlie cognitive deficits in epilepsy and targeting it pharmacologically may constitute a new avenue to enhance cognition.One Sentence SummaryImpaired input computations via aberrant dendritic spikes in chronic epilepsy degrade neuronal place codes and spatial memory