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...

As Huntington’s disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL, motor) and ventral posteromedial nucleus (VPM, somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and WT mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared to WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting membrane pote...

Anxiety is one of the most common psychiatric disorders diagnosed in the USA today. Like all mental illnesses, anxiety pathology includes genetic, molecular, somatic, and behavioral characteristics. Specific brain regions implicated in anxiety include the prefrontal cortex, amygdala, hippocampus, and hypothalamus. Together, these regions regulate fear-related learning and memory processes, and are innervated by neuronal projections that utilize glutamate and gamma-aminobutyric acid (GABA) as neurotransmitters. Neurotrophic factors such as brain derived neurotrophic factor (BDNF), are also implicated in anxiety. This review discusses the neuroepigenetics of the anxiety phenotype. While studying such changes is limited to post-mortem brain studies or peripheral tissue acquisition in humans, the use of animals to model anxiety phenotypes has made epigenetic research possible. In this review, we summarize and discuss a plethora of DNA methylation, histone modification, and associated gene expression difference...

Perampanel (PMP) is a third generation antiseizure drug reported to be a potent and selective noncompetitive negative allosteric modulator of one sub-family of ionotropic glutamate receptor (iGluR), the α-amino-3-hydroxy-S-methylisoxazole-4-propionic acid receptors (AMPARs). However, the recent structural resolution of AMPARs in complex with PMP revealed that its binding pocket is formed from residues that are largely conserved in two members of another family of iGluRs, the GluK4 and GluK5 kainate receptor (KAR) subunits. We show here that PMP inhibits both recombinant and neuronal KARs, contrary to the previous reports, and that the NAM activity requires GluK5 subunits to be channel constituents. PMP inhibited heteromeric GluK1/GluK5 and GluK2/GluK5 KARs at IC50 values comparable to that for AMPA receptors but was much less potent on homomeric GluK1 or GluK2 KARs. The auxiliary subunits Neto1 or Neto2 also made GluK2-containing KARs more sensitive to inhibition. Finally, PMP inhibited mouse neuronal KARs...

Deciding about courses of action involves minimizing costs and maximizing benefits. Decision neuroscience studies have implicated both the ventral and dorsal medial prefrontal cortex (vmPFC and dmPFC) in signaling goal value and action cost, but the precise functional role of these regions is still a matter of debate. Here, we suggest a more general functional partition that applies not only to decisions but also to judgments about goal value (expected reward) and action cost (expected effort). In this conceptual framework, cognitive representations related to options (reward value and effort cost) are dissociated from metacognitive representations (confidence and deliberation) related to solving the task (providing a judgment or making a choice). We used an original approach aiming at identifying consistencies across several preference tasks, from likeability ratings to binary decisions involving both attribute integration and option comparison. fMRI results in human male and female participants confirmed...

Cerebral ischemia–reperfusion injury in ischemic penumbra is accountable for poor outcome of ischemic stroke patients receiving recanalization therapy. Compelling evidence previously demonstrated a dual role of autophagy in stroke. This study aimed to understand the traits of autophagy in the ischemic penumbra and the potential mechanism that switches the dual role of autophagy. We found that autophagy induction by rapamycin and lithium carbonate performed before ischemia reduced neurological deficits and infarction, while autophagy induction after reperfusion had the opposite effect in the male murine middle cerebral artery occlusion/reperfusion model, both of which were eliminated in mice lacking autophagy (Atg7flox/flox; Nestin-Cre). Autophagic flux determination showed that reperfusion led to a blockage of axonal autophagosome retrograde transport in neurons, which then led to autophagic flux damage. Then, we found that ischemia–reperfusion induced changes in the protein levels of Sec22b and Ykt6 in ne...