Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). Aβ slowly adapting type 1 (SA1) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into Aβ SA1 LTMR action potentials that are transmitted to the central nervous system, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch of plantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory, but are relatively preserved in nearby hairy skin innervated by the ...

Previous research points to an association between retrieval-related activity in the medial prefrontal cortex (mPFC) and preservation of emotional information compared to co-occurring neutral information following sleep. Although the role of the mPFC in emotional memory likely begins at encoding, little research has examined how mPFC activity during encoding interacts with consolidation processes to enhance emotional memory. This issue was addressed in the present study using transcranial magnetic stimulation in conjunction with an emotional memory paradigm. Healthy young adults encoded negative and neutral scenes while undergoing concurrent TMS with a modified short intermittent theta burst stimulation (sTBS) protocol. Participants received stimulation to either the mPFC or an active control site (motor cortex) during the encoding phase. Recognition memory for scene components (objects and backgrounds) was assessed after a short (30-minute) and a long delay (24-hour, including a night of sleep) to obtain ...

Misophonia is a common disorder characterized by the experience of strong negative emotions of anger and anxiety in response to certain everyday sounds, such as those generated by other people eating, drinking and breathing. The commonplace nature of these ‘trigger’ sounds makes misophonia a devastating disorder for sufferers and their families. How such innocuous sounds trigger this response is unknown. Since most trigger sounds are generated by orofacial movements (e.g. chewing) in others, we hypothesized that the mirror neuron system related to orofacial movements could underlie misophonia. We analysed resting state fMRI (rs-fMRI) connectivity (N=33, 16 females) and sound-evoked fMRI responses (N=42, 29 females) in misophonia sufferers and controls. We demonstrate that, compared to controls, the misophonia group show no difference in auditory cortex responses to trigger sounds, but do show: (i) stronger rs-fMRI connectivity between both auditory and visual cortex and the ventral pre-motor cortex respons...

Protein phosphatase 2B (PP2B) is critical for synaptic plasticity and learning, but the molecular mechanisms involved remain unclear. Here we identified different types of proteins that interact with PP2B, among which structural proteins of the postsynaptic densities (PSDs) of Purkinje cells (PCs) in mice of either se. Deleting PP2B reduced expression of PSD proteins and the relative thickness of PSD at parallel fiber to PC synapses, whereas re-expression of inactive PP2B partly restored the impaired distribution of nanoclusters of PSD proteins, together indicating a structural role of PP2B. In contrast, lateral mobility of surface glutamate receptors solely depended on PP2B phosphatase activity. Finally, the level of motor learning co-varied with both the enzymatic and non-enzymatic function of PP2B. Thus, PP2B controls synaptic function and learning both through its action as a phosphatase and as a structural protein facilitating synapse integrity. SIGNIFICANCE STATEMENT Phosphatases are generally con...

Prolonged stress induces neural maladaptations in mesolimbic dopamine (DA) system and produces emotional and behavioral disorders. However, the effects of stress on activity of DA neurons are diverse and complex that hinge on the type, duration, intensity, and controllability of stressors. Here, controlling the duration, intensity, and type of the stressors to be identical, we observed effects of stressor controllability on the activity of substantia nigra compacta (SNc) DA neurons in mice. We found that both lack and loss of control over shock enhance the basal activity and intrinsic excitability of SNc DA neurons via modulation of Ih current, but not via corticosterone serum level. Moreover, loss of control over shock produces more significant enhancement in the basal activity of SNc DA neurons than that produced shock per se, and therefore attenuates the response to natural reward. This attenuation can be reversed by control over shock. These results indicate that although chronic stress per se tends to...

Pediatric traumatic brain injury (TBI) results in heightened risk for social deficits that can emerge during adolescence and adulthood. A moderate TBI in male and female rats on postnatal day 11 (equivalent to children below the age of 3) resulted in impairments in social novelty recognition, defined as the preference for interacting with a novel rat compared to a familiar rat, but not sociability, defined as the preference for interacting with a rat compared to an object in the three-chamber test when tested at 4-weeks (adolescence) and 8-weeks (adulthood) post-injury. The deficits in social recognition were not accompanied by deficits in novel object recognition memory and were associated with a decrease in the frequency of spontaneous inhibitory postsynaptic currents (IPSC) recorded from pyramidal neurons within layer II/III of the medial prefrontal cortex (mPFC). Whereas TBI did not affect the expression of oxytocin (OXT) or the oxytocin Receptor (OXT-R) mRNAs in the hypothalamus and mPFC respectively,...

The long cellular architecture of neurons requires regulation in part through transport and anchoring events to distribute intracellular organelles. During development, cellular and sub-cellular events such as organelle additions and their recruitment at specific sites on the growing axons occur over different time scales and often show inter-animal variability thus making it difficult to identify specific phenomena in population averages. To measure the variability in sub-cellular events such as organelle positions, we developed a microfluidic device to feed and immobilize C. elegans for high-resolution imaging over several days. The microfluidic device enabled long-term imaging of individual animals and allowed us to investigate organelle density using mitochondria as a testbed in a growing neuronal process in vivo . Sub-cellular imaging of an individual neuron in multiple animals, over 36 hours in our microfluidic device, shows the addition of new mitochondria along the neuronal process and an increase ...

Alpha oscillations in sensory cortex, under frontal control, desynchronize during attentive preparation. Here, in a selective attention study with simultaneous EEG in humans of either sex, we first demonstrate that diminished anticipatory alpha synchrony between the mid-frontal region of the dorsal attention network and ventral visual sensory cortex (frontal-sensory synchrony (FSS)) significantly correlates with greater task performance. Then, in a double-blind, randomized controlled study in healthy adults, we implement closed-loop neurofeedback of the anticipatory alpha FSS signal over ten days of training. We refer to this closed-loop experimental approach of rapid neurofeedback (NF) integrated within a cognitive task as cognitive neurofeedback (cNF). We show that cNF results in significant trial-by-trial modulation of the anticipatory alpha FSS measure during training, concomitant plasticity of stimulus-evoked alpha/theta responses, as well as transfer of benefits to response time improvements on a sta...

The ventral visual stream of the human brain is subdivided into patches with categorical stimulus preferences, like faces or scenes. However, the functional organization within these areas is less clear. Here, we used functional magnetic resonance imaging and vertex-wise tuning models to independently probe spatial and face-part preferences in the inferior occipital gyrus (IOG) of healthy adult males and females. The majority of responses were well explained by Gaussian population tuning curves for both retinotopic location and the preferred relative position within a face. Parameter maps revealed a common gradient of spatial and face-part selectivity, with the width of tuning curves drastically increasing from posterior to anterior IOG. Tuning peaks clustered more idiosyncratically, but were also correlated across maps of visual and face-space. Preferences for the upper visual field went along with significantly increased coverage of the upper half of the face, matching recently discovered biases in human...

The adult olfactory epithelium (OE) regenerates sensory neurons and non-sensory supporting cells from resident stem cells after injury. How supporting cells contribute to OE regeneration remains largely unknown. In this study, we elucidated a novel role of Ym2 (also known as Chil4 or Chi3l4), a chitinase-like protein expressed in supporting cells, in regulating regeneration of the injured OE in vivo in both male and female mice and cell proliferation/differentiation in OE colonies in vitro . We found that Ym2 expression was enhanced in supporting cells after OE injury. Genetic knockdown of Ym2 in supporting cells attenuated recovery of the injured OE while Ym2 overexpression by lentiviral infection accelerated OE regeneration. Similarly, Ym2 bidirectionally regulated cell proliferation and differentiation in OE colonies. Furthermore, anti-inflammatory treatment reduced Ym2 expression and delayed OE regeneration in vivo and cell proliferation/differentiation in vitro , which were counteracted by Ym2 overexp...