Transcriptional profiling of sequentially generated septal neuron fates

The septum is a ventral forebrain structure known to regulate innate behaviors. During embryonic development, septal neurons are produced in multiple proliferative areas from neural progenitors following transcriptional programs that are still largely unknown. Here, we use a combination of single cell RNA sequencing, histology and genetic models to address how septal neuron diversity is established during neurogenesis. We find that the transcriptional profiles of septal progenitors change along neurogenesis, coinciding with the generation of distinct neuron types. We characterize the septal eminence, an anatomically distinct and transient proliferative zone composed of progenitors with distinctive molecular profiles, proliferative capacity and fate potential compared to the rostral septal progenitor zone. We show that Nkx2.1-expressing septal eminence progenitors give rise to neurons belonging to at least three morphological classes, born in temporal cohorts that are distributed across different septal nuclei in a sequential fountain-like pattern. Our study provides insight into the molecular programs that control the sequential production of different neuronal types in the septum, a structure with important roles in regulating mood and motivation.

Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors

The neuropeptide oxytocin (OXT) is well recognized for eliciting anxiolytic effects and promoting social reward. However, emerging evidence shows that OXT increases aversive events. These seemingly inconsistent results may be attributable to the broad OXT receptor (OXTr) expression in the central nervous system. This study selectively activated septal neurons expressing OXTr using chemogenetics. We found that chemogenetic activation of septal OXTr neurons induced anxiety- but not depressive-like behavior. In addition, septal OXTr neurons projected dense fibers to the horizontal diagonal band of Broca (HDB), and selective stimulation of those HDB projections also elicited anxiety-like behaviors. We also found that septal OXTr neurons express the vesicular GABA transporter (vGAT) protein and optogenetic stimulation of septal OXTr projections to the HDB inactivated HDB neurons. Our data collectively reveal that septal OXTr neurons increase anxiety by projecting inhibitory GABAergic inputs to the HDB.

Transcriptional profiling of sequentially generated septal neuron fates

The septum is a ventral forebrain structure known to regulate innate behaviors. During embryonic development, septal neurons are produced in multiple proliferative areas from neural progenitors following transcriptional programs that are still largely unknown. Here, we use a combination of single cell RNA sequencing, histology and genetic models to address how septal neuron diversity is established during neurogenesis. We find that the transcriptional profiles of septal progenitors change along neurogenesis, coinciding with the generation of distinct neuron types. We characterize the septal eminence, a spatially distinct and transient proliferative zone composed of progenitors with distinctive molecular profiles, proliferative capacity and fate potential compared to the rostral septal progenitor zone. We show that Nkx2.1-expressing septal eminence progenitors give rise to neurons belonging to at least three morphological classes, born in temporal cohorts that are distributed across different septal nuclei in a sequential fountain-like pattern. Our study provides insight into the molecular programs that control the sequential production of different neuronal types in the septum, a structure with important roles in regulating mood and motivation.

Locomotion induced by medial septal glutamatergic neurons is linked to intrinsically generated persistent firing

Medial septal glutamatergic neurons are active during theta oscillations and locomotor activity. Prolonged optogenetic activation of medial septal glutamatergic neurons drives theta oscillations and locomotion for extended periods of time outlasting the stimulus duration. However, the cellular and circuit mechanisms supporting the maintenance of both theta oscillations and locomotion remain elusive. Specifically, it remains unclear whether the presence of theta oscillations is a necessary prerequisite for locomotion, and whether neuronal activity within the medial septum underlies its persistence. Here we show that a persistent theta oscillation can be induced by a brief transient activation of glutamatergic neurons. Moreover, persistent locomotion is initiated even if the theta oscillation is abolished by blocking synaptic transmission in the medial septum. We observe persistent spiking of medial septal neurons that outlasts the stimulus for several seconds, both in vivo and in vitro. This persistent activity is driven by intrinsic excitability of glutamatergic neurons.

Regionalisation of the callosal contribution to the barrel field activity in the mouse

Synchrony of neural activity among cortical areas arises from functional coupling between those areas. Such a strong synchrony characterises the two mouse barrel fields (BFs) when the animal is deeply anaesthetised or asleep. In these conditions, neurons in the two hemispheres depolarise (up-state) and hyperpolarise to their resting potential (down-state) in a remarkably coordinated fashion. Callosal glutamatergic axons provide a means to functionally couple supra- and infragranular neurons of the two BFs. However, little is known about their relationship with the BF grid-like architecture: Are they able to influence the activity of barrel and/or septal neurons? Are there specific barrels more sensitive to the contralateral activity? To respond to these questions, we localised and counted the BF cells positive to c-Fos (c-Fos + ) resulting from a contralateral whiskers deprivation when mice were free to explore a novel environment. In layer 4, we found a greater number of c-Fos + cells in septa compared to barrels, which mainly localised in the posterior and lateral aspects of the sensory-deprived BF. To learn more about such interhemispheric recruitment, we studied the propagation of slow-oscillatory activity in anaesthetised mice. We performed whole-cell patch-clamp in the ipsilateral BF while recording LFPs in the contralateral BF. In the BF lateral region, neurons showed faster oscillatory cycles, shorter up-state duration and faster down-to-up transitions compared to neurons recorded in BF regions with a sparser c-Fos signal, suggesting the reception of extra inputs in the former. We thus propose that the lateral BF is a critical sub-region for BFs activity-coupling.

Excitatory and inhibitory modulation of septal and striatal neurons during hippocampal sharp-wave ripple events

ABSTRACTSingle-units were recorded in hippocampus, septum, and striatum while freely behaving rats (n=3) ran trials in a T-maze task, and rested in a holding bucket between trials. During periods of motor inactivity, SWRs triggered excitatory responses from 28% (64/226) and inhibitory responses from 14% (31/226) of septal neurons. By contrast, only 4% (14/378) of striatal neurons were excited and 6% (24/378) were inhibited during SWRs. In both structures, SWR-responsive neurons exhibited greater spike coherence with hippocampal theta rhythm than neurons that did not respond to SWRs. In septum, neurons that were excited by SWRs fired at late phases of the theta cycle, whereas neurons that were inhibited by SWRs fired at early phases of the theta cycle. By contrast, SWR-responsive striatal neurons did not show consistent phase preferences during the theta cycle. A subset of SWR-responsive neurons in septum (55/95) and striatum (26/38) behaved as speed cells, with firing rates that were positively or negatively modulated by the rat’s running speed. In both structures, firing rates of most SWR-excited speed cells were positively modulated by running speed, whereas firing rates of most SWR-inhibited speed cells were negatively modulated by running speed. These findings are consistent with a growing body of evidence that SWRs can activate subcortical representations of motor actions in conjunction with hippocampal representations of places and states, which may be important for storing and retrieving values of state-action pairs during reinforcement learning and memory consolidation.