There is consensus that primary auditory cortex utilizes a combination of rate codes and temporally precise population codes to represent discreet auditory objects. During the response to auditory streams, forward suppression constrains cortical rate coding strategies, but it may also be well-positioned to enhance temporal coding strategies that rely upon synchronized firing across neural ensembles. Here, we exploited the rapid temporal dynamics of bat echolocation to investigate how forward suppression modulates the cortical ensemble representation of complex acoustic signals embedded in echo streams. We recorded from auditory cortex of anesthetized free-tailed bats while stimulating the auditory system with naturalistic biosonar pulse-echo sequences covering a range of pulse emission rates. As expected, increasing pulse repetition rate significantly reduced the number of spikes per echo stimulus, but it also increased spike timing precision and doubled the information gain. This increased spike-timing pr...

Taste buds contain multiple cell types, 2 of which mediate transduction of specific taste qualities: Type III cells transduce sour while Type II cells transduce either sweet, or bitter or umami. In order to discern the degree of interaction between different cell types and specificity of connectivity with the afferent nerve fibers, we employed serial blockface scanning electron microscopy through 5 circumvallate mouse taste buds. Points of contact between Type II and III cells are rare, and lack morphologically identifiable synapses, suggesting that interaction between these cell types does not occur via synapses. Of the 127 nerve fibers that make synaptic contacts with taste cells in the sampling volume, about 70% (n=91) synapse with only one taste cell while 32 fibers synapse exclusively with multiple Type II cells or multiple Type III cells. Our data do not rule out multimodal fibers innervating Type II cells of separate taste qualities. Notably, 4 fibers (∼3%) synapse with both Type II and Type III cel...

Ghrelin receptor, also known as growth hormone secretagogue receptor or GHS-R1a, is co-expressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D1 and D5 dopamine receptors (D1R and D5R) constitute the two D1-like receptor subtypes. Previous studies showed GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in ghrelin’s contribution to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R...

Recent studies suggest an important role of the principal inhibitory neurotransmitter GABA for motor performance in the context of aging. Nonetheless, as previous magnetic resonance spectroscopy (MRS) studies primarily reported resting-state GABA levels, much less is known about transient changes in GABA levels during motor task performance and how these relate to behavior and brain activity patterns. Therefore, we investigated GABA+ levels of left primary sensorimotor cortex (SM1) acquired before, during and after execution of a uni/bimanual action selection task in 30 (human) young (age 24.5 ± 4.1, 15 male) and 30 older adults (age 67.8 ± 4.9, 14 male). In addition to task-related MRS data, task-related fMRI data were acquired. Behavioral results indicated lower motor performance in older as opposed to young adults, particularly in complex task conditions. MRS results demonstrated lower GABA+ levels in older as compared to young adults. Furthermore, a transient task-related decrease of GABA+ levels was ...

The retrieval of recent and remote memories are thought to rely on distinct brain circuits and mechanisms. The retrosplenial cortex (RSC) is robustly activated during the retrieval of remotely acquired contextual fear memories (CFM), but the contribution of particular subdivisions [granular (RSG) versus agranular retrosplenial area (RSA)] and the circuit mechanisms through which they interact to retrieve remote memories remain unexplored. In this study, using both anterograde and retrograde viral tracing approaches, we identified excitatory projections from layer 5 pyramidal neurons of the RSG to the CA1 stratum radiatum/lacunosum-moleculare of the dorsal hippocampus and the superficial layers of the RSA in male mice. We found that chemogenetic or optogenetic inhibition of the RSG→CA1, but not the RSG→RSA, pathway selectively impairs the retrieval of remote CFM. Collectively, our results uncover a specific role for the RSG in remote CFM recall, and provide circuit evidence that RSG-mediated remote CFM retr...

Our eyes are constantly in motion and the various kinds of eye movements are closely linked to many aspects of human cognitive processing. Measuring all possible eye movements unobtrusively is not achievable with current methods. Video-based eye-trackers only measure rotational but not translational motion of the eye, require a calibration process relying on the participant’s self-report of accurate fixation, and do not work if vision of the eyeball is blocked. Scleral search coils attach physical weight on the eyeball and also do not measure translation. Here we describe a novel and fully automated method to use real-time Magnetic Resonance Imaging (MRI) for eye tracking. We achieved a temporal resolution sufficient to measure eye rotations and translations as short as those that occur within a blink and behind a closed eyelid. To demonstrate this method we measured the full extent of the blink-related eye movement for two individuals, suggesting that the eye approaches a holding position during lid closu...

A metanalysis identified Regulator of G protein Signaling 6 ( RGS6 ) as one of 23 loci with pleiotropic effects on four or more human psychiatric disorders. This finding is significant as it confirms/extends the findings of numerous other studies implicating RGS6 in CNS function and pathology. RGS6 is a highly conserved member of the RGS protein family whose cellular roles are likely affected by mRNA splicing and alternative domain inclusion/exclusion. Indeed, we previously identified multiple RGS6 splice variants predicted to produce 36 distinct protein isoforms containing either long (RGS6L) or short (RGS6S) N-terminal domains, an incomplete or intact GGL domain, and 9 alternative C-termini. Unfortunately, sequence similarities between the isoforms have made it difficult to confirm their individual existence and/or to determine their unique functions. Here, we developed 3 RGS6-specific antibodies that recognize all RGS6 protein isoforms (RGS6-fl), the N-terminus of RGS6L isoforms (RGS6-L), and an 18 amin...

In Drosophila , molecular pathways affecting longevity have been extensively studied. However, corresponding neurophysiological changes underlying aging-related functional and behavioral deteriorations remain to be fully explored. We examined different motor circuits in Drosophila across the lifespan and uncovered distinctive age-resilient and age-vulnerable trajectories in their established functional properties. In the giant-fiber (GF) and downstream circuit elements responsible for the jump-and-flight escape reflex, we observed relatively mild deterioration toward the end of lifespan. In contrast, more substantial age-dependent modifications were seen in the plasticity of GF afferent processing, specifically in use-dependence and habituation properties. In addition, there were profound changes in different afferent circuits that drive flight motoneuron activities, including flight pattern generation and seizure spike discharges evoked by electroconvulsive stimulation. Importantly, in high temperature (H...

The Parkinson’s disease (PD) risk gene GTP cyclohydrolase 1 (GCH1) catalyzes the rate-limiting step in tetrahydrobiopterin (BH4) synthesis, an essential cofactor in the synthesis of monoaminergic neurotransmitters. To investigate the mechanisms by which GCH1 deficiency may contribute to PD, we generated a loss of function zebrafish gch1 mutant ( gch1-/- ), using CRISPR/Cas technology. gch1-/- zebrafish develop marked monoaminergic neurotransmitter deficiencies by 5 dpf, movement deficits by 8 dpf and lethality by 12 dpf. Tyrosine hydroxylase protein levels were markedly reduced without loss of ascending dopaminergic (DAergic) neurons. L-Dopa treatment of gch1-/- larvae improved survival without ameliorating the motor phenotype. RNAseq of gch1-/- larval brain tissue identified highly upregulated transcripts involved in innate immune response. Subsequent experiments provided morphological and functional evidence of microglial activation in gch1-/-. The results of our study suggest that GCH1 deficiency may un...

Aphasia recovery after stroke depends on the condition of the remaining, extra-lesional brain network. Network control theory provides a unique, quantitative approach to assess the interaction between brain networks. In this longitudinal, large-scale, whole-brain connectome study, we evaluated whether controllability measures of language-related regions are associated with treated aphasia recovery. Using probabilistic tractography and controlling for the effects of structural lesions, we reconstructed whole-brain diffusion tensor imaging connectomes from 68 individuals (20 female, 48 male) with chronic post-stroke aphasia who completed a 3-week language therapy. Applying principles of network control theory, we computed regional 1) average and 2) modal controllability, which decode the ability of a region to 1) spread control input through the brain network and 2) to facilitate brain state transitions. We tested the relationship between pre-treatment controllability measures of 20 language-related left he...