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...

The superior colliculus (SC) is the midbrain center for integrating visual and multimodal sensory information. Neurons in the SC exhibit direction and orientation selectivity. Recent studies reported that neurons with similar preferences formed clusters in the mouse SC (Feinberg and Meister, 2014; Ahmadlou and Heimel, 2015; de Malmazet et al., 2018; Li et al., 2020) However, it remains controversial as to how these clusters are organized within the SC (Inayat et al., 2015; Chen et al., 2021). Here, we found that different brain states (i.e., awake or anesthetized with isoflurane) changed selectivity of individual SC neurons and organizations of the neuronal population in both male and female mice. Using two-photon Ca2+ imaging, we examined both individual neuronal responses and the spatial patterns of their population responses. Under isoflurane anesthesia, orientation selectivity increased and a larger number of orientation-selective cells were observed when compared to the awake condition, whereas the pr...

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...

Astrocytes are the most abundant glial cell in the brain and perform a wide range of tasks that support neuronal function and circuit activities. There is emerging evidence that astrocytes exhibit molecular and cellular heterogeneity; however, whether distinct subpopulations perform these diverse roles remains poorly defined. Here we show that the Lunatic Fringe-GFP (Lfng-GFP) bacteria artificial chromosome mouse line from both sexes specifically labels astrocyte populations within lamina III and IV of the dorsal spinal cord. Transcriptional profiling of Lfng-GFP+ astrocytes revealed unique molecular profiles, featuring an enriched expression of Notch- and Wnt- pathway components. Leveraging CRE-DOG viral tools, we ablated Lfng-GFP+ astrocytes, which decreased neuronal activity in lamina III and IV and impaired mechanosensation associated with light touch. Together, our findings identify Lfng-GFP+ astrocytes as a unique subpopulation that occupies a distinct anatomical location in the spinal cord and direc...

Fluorescence imaging is an indispensable method for analysis of diverse cellular and molecular processes, enabling e.g. detection of ions, second messengers or metabolites. Intensity-based approaches, however, are prone to artefacts introduced by changes in fluorophore concentrations. This drawback can be overcome by fluorescence lifetime imaging (FLIM) based on time-correlated single-photon counting. FLIM often necessitates long photon collection times, resulting in strong temporal binning of dynamic processes. Recently, rapidFLIM was introduced, exploiting ultra-low dead-time photodetectors together with rapid electronics. Here, we demonstrate the applicability of rapidFLIM, combined with new and improved correction schemes, for spatiotemporal fluorescence lifetime imaging of low-emission fluorophores in a biological system. Using tissue slices of hippocampi of mice of either sex, loaded with the Na+ indicator ING2, we show that improved rapidFLIM enables quantitative, dynamic imaging of neuronal Na+ sig...

Mild traumatic brain injury (mTBI) can initiate complex pathophysiological changes in the brain. Numerous cellular and molecular mechanisms underlying these pathologic changes are altered after injury, including those involved in energy utilization, excitotoxicity, ionic disturbances, and inflammation. It is thought that targeting multiple mechanisms may be necessary to produce meaningful reductions in brain pathology and to improve outcome. Previous studies have reported that the anti-diabetic drug metformin can also affect inflammatory, cell survival, and metabolic outcomes, possibly by acting on multiple targets and/or pathways. We therefore questioned whether metformin treatment can reduce pathology after repeat mild closed head injury (rmCHI) in male C57Bl/6 mice. We found that metformin, administered acutely after each head impact, resulted in markedly reduced white matter damage, astrogliosis, loss of hippocampal parvalbumin neurons, and improved mitochondrial function. In addition, both motor and c...

The co-chaperone FKBP51, encoded by the Fkbp5 gene, has been identified as central risk factor for anxiety-related disorders and stress system dysregulation. In the brain, the oval bed nucleus of the stria terminalis (ovBNST) has been implicated in stress-induced anxiety. However, the role of Fkbp5 in the ovBNST and its impact on anxiety-like behavior have remained unknown. Here we show in mice that Fkbp5 in the ovBNST is reactive to acute stress and co-expressed with the stress-regulated neuropeptides Tac2 and Crh . Subsequently, results obtained from viral-mediated manipulation indicate that Fkbp5 overexpression (OE) in the ovBNST results in an anxiolytic-like tendency regarding behavior and endocrinology, whereas a Fkbp5 knockout exposed a clear anxiogenic phenotype, indicating that native ovBNST expression and regulation is necessary for normal anxiety-related behavior. Notably, our data suggests that a stress-induced increase of Fkbp5 in the ovBNST may in fact have a protective role, leading to a tran...