Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.

In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.

K+ Channel Kv3.4 Is Essential for Axon Growth by Limiting the Influx of Ca2+ into Growth Cones.

Membrane excitability in the axonal growth cones of embryonic neurons influences axon growth. Voltage-gated K+ (Kv) channels are key factors in controlling membrane excitability, but whether they regulate axon growth remains unclear. Here, we report that Kv3.4 is expressed in the axonal growth cones of embryonic spinal commissural neurons, motoneurons, dorsal root ganglion neurons, retinal ganglion cells, and callosal projection neurons during axon growth. Our in vitro (cultured dorsal spinal neurons of chick embryos) and in vivo (developing chick spinal commissural axons and rat callosal axons) findings demonstrate that knockdown of Kv3.4 by a specific shRNA impedes axon initiation, elongation, pathfinding, and fasciculation. In cultured dorsal spinal neurons, blockade of Kv3.4 by blood depressing substance II suppresses axon growth via an increase in the amplitude and frequency of Ca2+ influx through T-type and L-type Ca2+ channels. Electrophysiological results show that Kv3.4, the major Kv channel in the axonal growth cones of embryonic dorsal spinal neurons, is activated at more hyperpolarized potentials and inactivated more slowly than it is in postnatal and adult neurons. The opening of Kv3.4 channels effectively reduces growth cone membrane excitability, thereby limiting excessive Ca2+ influx at subthreshold potentials or during Ca2+-dependent action potentials. Furthermore, excessive Ca2+ influx induced by an optogenetic approach also inhibits axon growth. Our findings suggest that Kv3.4 reduces growth cone membrane excitability and maintains [Ca2+]i at an optimal concentration for normal axon growth.SIGNIFICANCE STATEMENT Accumulating evidence supports the idea that impairments in axon growth contribute to many clinical disorders, such as autism spectrum disorders, corpus callosum agenesis, Joubert syndrome, Kallmann syndrome, and horizontal gaze palsy with progressive scoliosis. Membrane excitability in the growth cone, which is mainly controlled by voltage-gated Ca2+ (Cav) and K+ (Kv) channels, modulates axon growth. The role of Cav channels during axon growth is well understood, but it is unclear whether Kv channels control axon outgrowth by regulating Ca2+ influx. This report shows that Kv3.4, which is transiently expressed in the axonal growth cones of many types of embryonic neurons, acts to reduce excessive Ca2+ influx through Cav channels and thus permits normal axon outgrowth.

Hippocampal firing fields anchored to a moving object predict homing direction during path-integration-based behavior.

Homing based on path integration (H-PI) is a form of navigation in which an animal uses self-motion cues to keep track of its position and return to a starting point. Despite evidence for a role of the hippocampus in homing behavior, the hippocampal spatial representations associated with H-PI are largely unknown. Here we developed a homing task (AutoPI task) that required a mouse to find a randomly placed lever on an arena before returning to its home base. Recordings from the CA1 area in male mice showed that hippocampal neurons remap between random foraging and AutoPI task, between trials in light and dark conditions, and between search and homing behavior. During the AutoPI task, approximately 25% of the firing fields were anchored to the lever position. The activity of 24% of the cells with a lever-anchored field predicted the homing direction of the animal on each trial. Our results demonstrate that the activity of hippocampal neurons with object-anchored firing fields predicts homing behavior.

Inhibitory projections connecting the dentate gyri in the two hemispheres support spatial and contextual memory.

The dentate gyrus (DG) receives substantial input from the homologous brain area of the contralateral hemisphere. This input is by and large excitatory. Viral-tracing experiments provided anatomical evidence for the existence of GABAergic connectivity between the two DGs, but the function of these projections has remained elusive. Combining electrophysiological and optogenetic approaches, we demonstrate that somatostatin-expressing contralateral DG (SOM+ cDG)-projecting neurons preferentially engage dendrite-targeting interneurons over principal neurons. Single-unit recordings from freely moving mice reveal that optogenetic stimulation of SOM+ cDG projections modulates the activity of GABAergic neurons and principal neurons over multiple timescales. Importantly, we demonstrate that optogenetic silencing of SOM+ cDG projections during spatial memory encoding, but not during memory retrieval, results in compromised DG-dependent memory. Moreover, optogenetic stimulation of SOM+ cDG projections is sufficient to disrupt contextual memory recall. Collectively, our findings reveal that SOM+ long-range projections mediate inter-DG inhibition and contribute to learning and memory.

Diazepam binding inhibitor governs neurogenesis of excitatory and inhibitory neurons during embryonic development via GABA signaling.

Of the neurotransmitters that influence neurogenesis, gamma-aminobutyric acid (GABA) plays an outstanding role, and GABA receptors support non-synaptic signaling in progenitors and migrating neurons. Here, we report that expression levels of diazepam binding inhibitor (DBI), an endozepine that modulates GABA signaling, regulate embryonic neurogenesis, affecting the long-term outcome regarding the number of neurons in the postnatal mouse brain. We demonstrate that DBI is highly expressed in radial glia and intermediate progenitor cells in the germinal zones of the embryonic mouse brain that give rise to excitatory and inhibitory cells. The mechanism by which DBI controls neurogenesis involves its action as a negative allosteric modulator of GABA-induced currents on progenitor cells that express GABAA receptors containing γ2 subunits. DBI's modulatory effect parallels that of GABAA-receptor-mediating signaling in these cells in the proliferative areas, reflecting the tight control that DBI exerts on embryonic neurogenesis.

Two septal-entorhinal GABAergic projections differentially control coding properties of spatially tuned neurons in the medial entorhinal cortex.

Septal parvalbumin-expressing (PV+) and calbindin-expressing (CB+) projections inhibit low-threshold and fast-spiking interneurons, respectively, in the medial entorhinal cortex (MEC). We investigate how the two inputs control neuronal activity in the MEC in freely moving mice. Stimulation of PV+ and CB+ terminals causes disinhibition of spatially tuned MEC neurons, but exerts differential effects on temporal coding and burst firing. Thus, recruitment of PV+ projections disrupts theta-rhythmic firing of MEC neurons, while stimulation of CB+ projections increases burst firing of grid cells and enhances phase precession in a cell-type-specific manner. Inactivation of septal PV+ or CB+ neurons differentially affects context, reference, and working memory. Together, our results reveal how specific connectivity of septal GABAergic projections with MEC interneurons translates into differential modulation of MEC neuronal coding.