Fragile X Syndrome is a neurodevelopmental disorder and the most common monogenic cause of intellectual disability, autism spectrum disorders, and anxiety disorders. Loss of fragile x mental retardation protein results in disruptions of synaptic development during a critical period of circuit formation in the BLA. However, it is unknown how these alterations impact microcircuit development and function. Using a combination of electrophysiologic and behavioral approaches in both male ( Fmr1 -/y) and female ( Fmr1 −/−) mice, we demonstrate that principal neurons in the Fmr1 KO BLA exhibit hyperexcitability during a sensitive period in amygdala development. This hyperexcitability contributes to increased excitatory gain in fear-learning circuits. Further, synaptic plasticity is enhanced in the BLA of Fmr1 KO mice. Behavioral correlation demonstrates that fear-learning emerges precociously in the Fmr1 KO mouse. Early life 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin-3ol intervention ameliorates fear-learning in ...

Although the neural basis of working memory (WM) capacity is often studied by exploiting interindividual differences, capacity may also differ across memory materials within a given individual. Here, we exploit the content dependence of WM capacity as a novel approach to investigate the oscillatory correlates of WM capacity, focusing on posterior 9–12 Hz alpha activity during retention. We recorded scalp electroencephalography (EEG) while male and female human participants performed WM tasks with varying memory loads (two vs. four items) and materials (English letters vs. regular shapes vs. abstract shapes). First, behavioral data confirmed that memory capacity was fundamentally content dependent; capacity for abstract shapes plateaued at around two, whereas the participants could remember more letters and regular shapes. Critically, content-specific capacity was paralleled in the degree of attenuation of EEG-alpha activity that plateaued in a similar content-specific manner. Although we observed greater a...

The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here, we identify a genetic intersection ( Cck-Cre and Brn3cCKOAP ) that selectively labels transient Suppressed-by-Contrast (tSbC) RGCs, a member of an evolutionarily conserved functionally mysterious RGC subclass. We find that tSbC RGCs selectively innervate the dorsolateral geniculate nucleus (dLGN) and ventrolateral geniculate nucleus (vLGN) of the thalamus, the superior colliculus (SC), and the nucleus of the optic tract (NOT) in mice of either sex. They binocularly innervate dLGN and vLGN but project only contralaterally to SC and N...

Dorsal raphe (DR) 5-HT neurons regulate sleep–wake transitions. Previous studies demonstrated that single-unit activity of DR 5-HT neurons is high during wakefulness, decreases during non-rapid eye movement (NREM) sleep, and ceases during rapid eye movement (REM) sleep. However, characteristics of the population-level activity of DR 5-HT neurons, which influence the entire brain, are largely unknown. Here, we measured population activities of 5-HT neurons in the male and female mouse DR across the sleep–wake cycle by ratiometric fiber photometry. We found a slow oscillatory activity of compound intracellular Ca2+ signals during NREM sleep. The trough of the concave 5-HT activity increased across sleep progression, but 5-HT activity always returned to that seen during the wake period. When the trough reached a minimum and remained there, REM sleep was initiated. We also found a unique coupling of the oscillatory 5-HT activity and wideband EEG power fluctuation. Furthermore, optogenetic activation of 5-HT ne...

Costanza Angelini, Alessandro Morellato, Annalisa Alfieri, Lisa Pavinato, Tiziana Cravero, et al. (see pages [7183–7200][1]) The postsynaptic density (PSD) of excitatory synapses contains an extraordinary number of proteins, including AMPA and NMDA receptors, accessory proteins that regulate

Task representations are critical for cognitive control and adaptive behavior. The hierarchical organization of task representations allows humans to maintain goals, integrate information across varying contexts, and select potential responses. In this study we characterized the structure and interactive dynamics of task representations that facilitate cognitive control. Human participants (both males and females) performed a hierarchical task that required them to select a response rule while considering the contingencies from different contextual inputs. By applying time- and frequency-resolved representational similarity analysis to human electroencephalography data, we characterized properties of task representations that are otherwise difficult to observe. We found that participants formed multiple representations of task-relevant contexts and features from the presented stimuli, beyond simple stimulus–response mappings. These disparate representations were hierarchically structured, with higher-order...

The mitochondrial anchor syntaphilin (SNPH) is a key mitochondrial protein normally expressed in axons to maintain neuronal health by positioning mitochondria along axons for metabolic needs. However, in 2019 we discovered a novel form of excitotoxicity that results when SNPH is misplaced into neuronal dendrites in disease models. A key unanswered question about this SNPH excitotoxicity is the pathologic molecules that trigger misplacement or intrusion of SNPH into dendrites. Here, we identified two different classes of pathologic molecules that interact to trigger dendritic SNPH intrusion. Using primary hippocampal neuronal cultures from mice of either sex, we demonstrated that the pro-inflammatory cytokine IL-1β interacts with NMDA to trigger SNPH intrusion into dendrites. First, IL-1β and NMDA each individually triggers dendritic SNPH intrusion. Second, IL-1β and NMDA do not act independently but interact. Thus, blocking NMDAR by the antagonist MK-801 blocks IL-1β from triggering dendritic SNPH intrusio...

To what extent is the size of the BOLD response influenced by factors other than neural activity? In a reanalysis of three neuroimaging datasets (male and female human participants), we find large systematic inhomogeneities in the BOLD response magnitude in primary visual cortex (V1): stimulus-evoked BOLD responses, expressed in units of percent signal change, are up to 50% larger along the representation of the horizontal meridian than the vertical meridian. To assess whether this surprising effect can be interpreted as differences in local neural activity, we quantified several factors that potentially contribute to the size of the BOLD response. We find relationships between BOLD response magnitude and cortical thickness, curvature, depth, and macrovasculature. These relationships are consistently found across subjects and datasets and suggest that variation in BOLD response magnitudes across cortical locations reflects, in part, differences in anatomy and vascularization. To compensate for these factor...

Adaptive behavior requires the ability to appropriately react to action errors. Post-error slowing (PES) of response times is one of the most reliable phenomena in human behavior. It has been proposed that PES is partially achieved through inhibition of the motor system. However, there is no direct evidence for this link, or indeed, that the motor system is physiologically inhibited after errors altogether. Here, we used transcranial magnetic stimulation and electromyography to measure corticospinal excitability (CSE) across four experiments using a Simon task, in which female and male human participants sometimes committed errors. Errors were followed by reduced CSE at two different time points and in two different modes. Shortly after error commission (250 ms), CSE was broadly suppressed (i.e., even task-unrelated motor effectors were inhibited). During the preparation of the subsequent response, CSE was specifically reduced at task-relevant effectors only. This latter effect was directly related to PES,...

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults' AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater cent...