The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds (HWTs), orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the kappa-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia which could however be reversed by intra-RVM microinjection of the...

Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signalling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeACAM neurons) and project to the lateral parabrachial nucleus (LPBN), a brainstem region known for its critical role in distributing nociceptive and other aversive signals throughout the brain. In male Sprague-Dawley rats, we show that CeACAM-LPBN neurons are GABAergic and mostly express somatostatin. In anaesthetised rats, optogenetic stimulation of CeACAM-LPBN projections inhibited responses of LPBN neurons evoked by electrical activation of Aδ- and C-fibre primary afferents; this inhibition could be blocked by intra-LPBN application of the GABAA receptor antagonist bicuculline. CeACAM-LPBN stimulation also dampened LPBN responses to noxious mechanical, thermal, and chemical stimuli. In behaving...

Classical forward and reverse mouse genetics require germline mutations and, thus, are unwieldy to study sleep functions of essential genes or redundant pathways. It is also time-consuming to conduct electroencephalogram/electromyogram-based mouse sleep screening owing to labor-intensive surgeries and genetic crosses. Here, we describe a highly accurate SleepV (video) system and adeno-associated virus (AAV)-based adult brain chimeric (ABC)-expression/knockout (KO) platform for somatic genetics analysis of sleep in adult male or female mice. A pilot ABC screen identifies CREB and CRTC1, of which constitutive or inducible expression significantly reduces quantity and/or quality of non-rapid eye movement sleep. Whereas ABC-KO of exon 13 of Sik3 by AAV-Cre injection in Sik3-E13flox/flox adult mice phenocopies Sleepy (Sik3Slp/+) mice, ABC-CRISPR of Slp/Sik3 reverses hypersomnia of Sleepy mice, indicating a direct role of SLP/SIK3 kinase in sleep regulation. Multiplex ABC-CRISPR of both orexin/hypocretin recepto...

Alzheimer’s disease (AD) is histopathologically characterized by Aβ plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing non-amyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages o...

We used pupillometry to evaluate the effects of attention cueing on perceptual bi-stability, as reported by adult human observers. Perceptual alternations and pupil diameter were measured during two forms of rivalry, generated by presenting a white and a black disk to the two eyes (binocular rivalry) or splitting the disks between eyes (interocular grouping rivalry). In line with previous studies, we found that subtle pupil size modulations (about 0.05 mm) tracked alternations between exclusive dominance phases of the black or white disk. These pupil responses were larger for perceptually stronger stimuli: presented to the dominant eye or with physically higher luminance contrast. However, cueing of endogenous attention to one of the rivaling percepts did not affect pupil modulations during exclusive dominance phases. This was observed despite the reliable effects of endogenous attention on perceptual dominance, which shifted in favor of the cued percept by about 10%. The results were comparable for binocu...

Fear-based disorders such as posttraumatic stress disorder (PTSD) steepen age-related cognitive decline and doubles the risk for developing Alzheimer’s disease. Due to the seemingly hyperactive properties of fear memories, PTSD symptoms can worsen with age. Perturbations in the synaptic circuitry supporting fear memory extinction are key neural substrates of PTSD. The basolateral amygdala (BLA) is a medial temporal lobe structure critical in the encoding, consolidation, and retrieval of fear memories. As little is known about fear extinction memory and BLA synaptic dysfunction within the context of aging and AD, the goal of this study was to investigate how fear extinction memory deficits and basal amygdaloid nucleus (BA) synaptic dysfunction differentially associate in non-pathological aging and AD in the TgF344AD (TgAD) rat model of AD. Young, middle-aged, and older-aged WT and TgAD rats were trained on a delay fear conditioning and extinction procedure prior to ex vivo extracellular field potential reco...

Neural adaptation enables the brain to efficiently process sensory signals despite large changes in background noise. Previous studies have established that recent background spectro- or spatio-temporal statistics scale neural responses to sensory stimuli via a canonical normalization computation, which is conserved among species and sensory domains. In the auditory pathway, one major form of normalization, termed contrast gain control, presents as decreasing instantaneous firing-rate gain with increasing spectrotemporal contrast. Despite this gain rescaling, mean firing-rates in auditory cortex become invariant to sound level contrast, termed contrast invariance. The underlying neuromodulatory mechanisms of these two phenomena remain unknown. To study these mechanisms in male and female mice, we used a 2-photon calcium imaging preparation in layer 2/3 neurons of primary auditory cortex (A1), along with pharmacological and genetic knockout approaches. We found that neuromodulatory cortical synaptic zinc si...

Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision making and MFC supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques ( Macaca mulatta ) with crossed surgical disconnection of the amygdala and either MFC (MFC x AMY, n =4) or OFC (OFC x AMY, n =4) to a group of unoperated controls (CON, n =5). All monkeys were assessed for their performance on two tasks to measure: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest, and (2) object choices based on current food value using reinforcer deva...

Neuroscience is not just for neuroscientists. It is for everyone, but it is absent from our high schools. High schools have a huge investment in STEM, but do not include neuroscience, even though neuroscience is more interesting and relevant to a person’s daily life than most other sciences. However, neuroscience opportunities are increasing for teenagers outside the standard curriculum. Significance Statement The neuroscience community and the education community must provide more opportunities in neuroscience education for teenagers.

Although visual object recognition is well-studied and relatively well understood, much less is known about how shapes are recognized by touch and how such haptic stimuli might be compared to visual shapes. One might expect that the processes of visual and haptic object recognition engage similar brain structures given the advantages of avoiding redundant brain circuitry and indeed there is some evidence that this is the case. A potentially fruitful approach to understanding the differences in how shapes might be neurally represented is to find an algorithmic method of comparing shapes which agrees with human behavior and determine whether that method differs between different modality conditions. If not, it would provide further evidence for a shared representation of shape. We recruited human participants to perform a one-back same-different visual and haptic shape comparison task both within (i.e., comparing two visual shapes or two haptic shapes) and across (i.e., comparing visual with haptic shapes) m...