Peripheral nerves are divided into multiple branches leading to divergent synaptic targets. This poses a remarkable challenge for regenerating axons as they select their original trajectory at nerve branch-points. Despite implications for functional regeneration, the molecular mechanisms underlying target selectivity are not well characterized. Danio Rerio (zebrafish) motor nerves are composed of a ventral and a dorsal branch that diverge at a choice-point, and we have previously shown that regenerating axons faithfully select their original branch and targets. Here we identify Robo2 as a key regulator of target-selective regeneration (sex of experimental subjects unknown). We demonstrate that Robo2 function in regenerating axons is required and sufficient to drive target-selective regeneration, and that Robo2 acts in response to glia located precisely where regenerating axons select the branch-specific trajectory to prevent and correct axonal errors. Combined our results reveal a glia derived mechanism th...

Aging is often associated with cognitive decline and recurrent cellular and molecular impairments. While life-long caloric restriction (CR) may delay age-related cognitive deterioration as well as the onset of neurological disease, recent studies suggest that late-onset, short-term intermittent fasting (IF), may show comparable beneficial effects as those of life-long CR to improve brain health. We used a new optogenetic aging model to study the effects of late-onset (>18 months), short-term (4-6 weeks) IF on age-related changes in GABAergic synaptic transmission, intracellular calcium (Ca2+) buffering and cognitive status. We utilized male mice from a bacterial artificial chromosome (BAC) transgenic mouse line with stable expression of the channelrhodopsin-2 (ChR2) variant H134R [VGAT-ChR2(H134R)-EYFP] in a reduced synaptic preparation that allows for specific optogenetic light stimulation on GABAergic synaptic terminals across aging. We performed quantal analysis using the method of failures in this mode...

Space-specific neurons in the owl's midbrain form a neural map of auditory space, which supports sound-orienting behavior. Previous work proposed that a population vector (PV) readout of this map, implementing statistical inference, predicts the owl's sound localization behavior. This model also predicts the frontal localization bias normally observed and how sound-localizing behavior changes when the signal-to-noise ratio varies, based on the spread of activity across the map. However, the actual distribution of population activity and whether this pattern is consistent with premises of the PV readout model on a trial-by-trial basis remains unknown. To answer these questions, we investigated whether the population response profile across the midbrain map in the optic tectum of the barn owl matches these predictions using in vivo multielectrode array recordings. We found that response profiles of recorded subpopulations are sufficient for estimating the stimulus interaural time difference using responses f...

Most of our knowledge about human emotional memory comes from animal research. Based on this work, the amygdala is often labeled the brain's “fear center”, but it is unclear to what degree neural circuitries underlying fear and extinction learning are conserved across species. Neuroimaging studies in humans yield conflicting findings, with many studies failing to show amygdala activation in response to learned threat. Such null findings are often treated as resulting from MRI-specific problems related to measuring deep brain structures. Here we test this assumption in a mega-analysis of three studies on fear acquisition ( n = 98; 68 female) and extinction learning ( n = 79; 53 female). The conditioning procedure involved the presentation of two pictures of faces and two pictures of houses: one of each pair was followed by an electric shock [a conditioned stimulus (CS+)], the other one was never followed by a shock (CS–), and participants were instructed to learn these contingencies. Results revealed widesp...

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual difference...

When listening to speech, our brain responses time lock to acoustic events in the stimulus. Recent studies have also reported that cortical responses track linguistic representations of speech. However, tracking of these representations is often described without controlling for acoustic properties. Therefore, the response to these linguistic representations might reflect unaccounted acoustic processing rather than language processing. Here, we evaluated the potential of several recently proposed linguistic representations as neural markers of speech comprehension. To do so, we investigated EEG responses to audiobook speech of 29 participants (22 females). We examined whether these representations contribute unique information over and beyond acoustic neural tracking and each other. Indeed, not all of these linguistic representations were significantly tracked after controlling for acoustic properties. However, phoneme surprisal, cohort entropy, word surprisal, and word frequency were all significantly tra...

Years of basic neuroscience on the modulation of the small circuits found in the crustacean stomatogastric ganglion have led us to study the effects of temperature on the motor patterns produced by the stomatogastric ganglion. While the impetus for this work was the study of individual variability in the parameters determining intrinsic and synaptic conductances, we are confronting substantial fluctuations in the stability of the networks to extreme temperature; these may correlate with changes in ocean temperature. Interestingly, when studied under control conditions, these wild-caught animals appear to be unchanged, but it is only when challenged by extreme temperatures that we reveal the consequences of warming oceans.

Neurotoxic HIV-1 viral proteins contribute to the development of HIV-associated neurocognitive disorder (HAND), the prevalence of which remains high (30–50%) with no effective treatment available. Estrogen is a known neuroprotective agent; however, the diverse mechanisms of estrogen action on the different types of estrogen receptors is not completely understood. In this study, we determined the extent to which and mechanisms by which 17α-estradiol (17αE2), a natural less-feminizing estrogen, offers neuroprotection against HIV-1 gp120-induced neuronal injury. Endolysosomes are important for neuronal function, and endolysosomal dysfunction contributes to HAND and other neurodegenerative disorders. In hippocampal neurons, estrogen receptor α (ERα) is localized to endolysosomes and 17αE2 acidifies endolysosomes. ERα knockdown or overexpressing an ERα mutant that is deficient in endolysosome localization prevents 17αE2-induced endolysosome acidification. Furthermore, 17αE2-induced increases in dendritic spine ...