Retinal bipolar cells (BCs) compose the canonical vertical excitatory pathway that conveys photoreceptor output to inner retinal neurons. Although synaptic transmission from BC terminals is thought to rely almost exclusively on Ca2+ influx through voltage-gated Ca2+ (CaV) channels mediating L-type currents, the molecular identity of CaV channels in BCs is uncertain. Therefore, we combined molecular and functional analyses to determine the expression profiles of CaV α1, β, and α2δ subunits in mouse rod bipolar (RB) cells, BCs from which the dynamics of synaptic transmission are relatively well-characterized. We found significant heterogeneity in CaV subunit expression within the RB population from mice of either sex, and significantly, we discovered that transmission from RB synapses was mediated by Ca2+ influx through P/Q-type (CaV2.1) and N-type (CaV2.2) conductances as well as the previously-described L-type (CaV1) and T-type (CaV3) conductances. Furthermore, we found both CaV1.3 and CaV1.4 proteins loca...

Post-traumatic epilepsy (PTE) and behavioral comorbidities frequently develop after traumatic brain injury (TBI). Aberrant neurogenesis of dentate granule cells (DGCs) after TBI may contribute to the synaptic reorganization that occurs in PTE, but how neurogenesis at different times relative to the injury contributes to feedback inhibition and recurrent excitation in the dentate gyrus is unknown. Thus, we examined whether DGCs born at different postnatal ages differentially participate in feedback inhibition and recurrent excitation in the dentate gyrus using the controlled cortical impact (CCI) model of TBI. Both sexes of transgenic mice expressing channelrhodopsin2 (ChR2) in postnatally born DGCs were used for optogenetic activation of three DGC cohorts: postnatally early born DGCs, or those born just before or after CCI. We performed whole-cell patch-clamp recordings from ChR2-negative, mature DGCs and parvalbumin-expressing basket cells (PVBCs) in hippocampal slices to determine whether optogenetic act...

A particularly elusive puzzle concerning the hippocampus is how the structural differences along its long, anteroposterior axis might beget meaningful functional differences, particularly in terms of the granularity of information processing. One measure posits to quantify this granularity by calculating the average statistical independence of the BOLD signal across neighboring voxels, or inter-voxel similarity (IVS), and has shown the anterior hippocampus to process coarser-grained information than the posterior hippocampus. This measure, however, has yielded opposing results in studies of developmental and healthy aging samples, which also varied in fMRI acquisition parameters and hippocampal parcellation methods. In order to reconcile these findings, we measured IVS across two separate resting-state fMRI acquisitions and compared the results across many of the most widely used parcellation methods in a large young-adult sample of male and female humans (Acquisition 1, N = 233; Acquisition 2, N = 176). F...

Commissural axons initially respond to attractive signals at the midline, but once they cross, they become sensitive to repulsive cues. In insects and mammals, negative regulation of the surface expression of Roundabout (Robo) receptors prevents premature response to Slit. We previously identified two mammalian Nedd4 interacting proteins, Ndfip1 and Ndfip2, that act analogously to Drosophila Commissureless (Comm) to recruit mammalian Robo1 to late endosomes. However, whether Nedd4 E3 ubiquitin ligases are required for Ndfip-mediated Robo1 regulation and midline axon crossing in vivo is not known. Here we show using in vitro biochemical techniques and genetic analysis using embryonic mice of either sex that Nedd4-1 and Nedd4-2 are specifically required for Robo1 regulation and spinal commissural axon guidance. Biochemical data indicate that Robo1, Ndfip and Nedd4 form a ternary protein complex that depends on the presence of Ndfip, and these interactions are required for Robo1 endosomal sorting, ubiquitylat...

The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here, we identify a genetic intersection ( Cck-Cre and Brn3cCKOAP ) that selectively labels transient Suppressed-by-Contrast (tSbC) RGCs, a member of an evolutionarily conserved functionally mysterious RGC subclass. We find that tSbC RGCs selectively innervate the dorsolateral geniculate nucleus (dLGN) and ventrolateral geniculate nucleus (vLGN) of the thalamus, the superior colliculus (SC), and the nucleus of the optic tract (NOT) in mice of either sex. They binocularly innervate dLGN and vLGN but project only contralaterally to SC and N...

Terrestrial locomotion requires coordinated bilateral activation of limb muscles, with left–right alternation in walking or running, and synchronous activation in hopping or skipping. The neural mechanisms involved in interlimb coordination at birth are well known in different mammalian species, but less so in humans. Here, 46 neonates (of either sex) performed bilateral and unilateral stepping with one leg blocked in different positions. By recording EMG activities of lower-limb muscles, we observed episodes of left–right alternating or synchronous coordination. In most cases, the frequency of EMG oscillations during sequences of consecutive steps was approximately similar between the two sides, but in some cases it was considerably different, with episodes of 2:1 interlimb coordination and episodes of activity deletions on the blocked side. Hip position of the blocked limb significantly affected ipsilateral, but not contralateral, muscle activities. Thus, hip extension backward engaged hip flexor muscle,...

The PFC is thought to be the region where remote memory is recalled. However, the neurotrophic receptors that underlie the remote memory remain largely unknown. Here, we benefited from auto-assembly split Cre to accomplish the neural projection-specific recombinase activity without spontaneous leakage. Deletion of tropomyosin receptor kinase B (TrkB) in neurons projecting from the medial entorhinal cortex to the mPFC displayed reduced remote memory recall from the male mice, but the recent recall was intact. We found that the TrkB deletion attenuates the participation of mPFC cells in the remote fear memory recall. The disruption of remote recall was attributed to reduced reactivation of cells in the mPFC. Notably, TrkB deletion seriously inhibited experience-dependent maturation of oligodendroglia in the PFC, resulting in defects in remote recall that were rescued by clemastine administration. Together, our data suggest that TrkB in intercortical circuits functions in remote memory consolidation. SIGNIFI...

Large glutamatergic, somatic synapses mediate temporally precise information transfer. In the ventral nucleus of the lateral lemniscus, an auditory brainstem nucleus, the signal of an excitatory large somatic synapse is sign inverted to generate rapid feedforward inhibition with high temporal acuity at sound onsets, a mechanism involved in the suppression of spurious frequency information. The mechanisms of the synaptically driven input–output functions in the ventral nucleus of the lateral lemniscus are not fully resolved. Here, we show in Mongolian gerbils of both sexes that, for stimulation frequencies up to 200 Hz, the EPSC kinetics together with short-term plasticity allow for faithful transmission with only a small increase in latency. Glutamatergic currents are exclusively mediated by AMPARs and NMDARs. Short-term plasticity is frequency-dependent and composed of an initial facilitation followed by depression. Physiologically relevant output generation is limited by the decrease in synaptic conducta...

Aggressive behavior is one of the most conserved social interactions in nature and serves as a crucial evolutionary trait. Serotonin (5-HT) plays a key role in the regulation of our emotions, such as anxiety and aggression, but which molecules and mechanisms in the serotonergic system are involved in violent behavior are still unknown. In this study, we show that deletion of the P/Q-type calcium channel selectively from serotonergic neurons in the dorsal raphe nuclei (DRN) augments aggressive behavior in male mice, while anxiety is not affected. These mice demonstrated increased induction of the immediate early gene c-fos and in vivo serotonergic firing activity in the DRN. The ventrolateral part of the ventromedial hypothalamus is also a prominent region of the brain mediating aggression. We confirmed a monosynaptic projection from the DRN to the ventrolateral part of the ventromedial hypothalamus, and silencing these projections with an inhibitory designer receptor exclusively activated by a designer dru...

Migraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at cortical synapses between pyramidal cells (PCs) and fast-spiking interneurons (FS INs) in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory (E/I) balance in specific circuits is a key pathogenic mechanism. Here, we investigated the cortical layer 2/3 (L2/3) feedback inhibition microcircuit involving somatostatin-expressing (SOM) INs in FHM1 mice of both sexes carrying a gain-of-function mutation in CaV2.1. Unitary inhibitory neurotransmission at SOM IN-PC synapses was unaltered while excitatory neurotransmission at both PC-SOM IN and PC-PC synapses was enhanced, because of increased probability of glutamate release, in FHM1 mice. Short-term s...