Visual search has traditionally been studied in cognitive and perceptual paradigms, but little is known about how it contributes to visuomotor performance. We have developed a novel computational model to examine how three underlying processes of visual search (spatial planning, working memory, and peripheral visual processing) contribute to visual search during a visuomotor task. We show that deficits integrating spatial planning and working memory underlie abnormal performance in stroke survivors with frontoparietal damage.
The inability to extinguish a traumatic memory is a key aspect of post-traumatic stress disorder (PTSD). While PTSD affects 10–20% of individuals who experience a trauma, women are particularly susceptible to developing the disorder. Despite this notable female vulnerability, few studies have investigated this particular resistance to fear extinction observed in females. Similar to humans, rodent models of Pavlovian fear learning and extinction show a wide range of individual differences in fear learning and extinction, although female rodents are considerably understudied. Therefore, the present study examined individual differences in fear responses, including freezing behavior and ultrasonic vocalizations (USVs), of female Long–Evans rats during acquisition of fear conditioning and cued fear extinction. Similar to prior studies in males, female rats displayed individual variation in freezing during cued fear extinction and were divided into extinction competent (EC) and extinction resistant (ER) phenotypes. Differences in freezing between ER and EC females were accompanied by shifts in rearing during extinction, but no darting was seen in any trial. Freezing behavior during fear learning did not differ between the EC and ER females. Vocalizations emitted in the 22 and 50 kHz ranges during fear learning and extinction were also examined. Unlike vocalizations seen in previous studies in males, very few 22 kHz distress vocalizations were emitted by female rats during fear acquisition and extinction, with no difference between ER and EC groups. Interestingly, all female rats produced significant levels of 50 kHz USVs, and EC females emitted significantly more 50 kHz USVs than ER rats. This difference in 50 kHz USVs was most apparent during initial exposure to the testing environment. These results suggest that like males, female rodents show individual differences in both freezing and USVs during fear extinction, although females appear to vocalize more in the 50 kHz range, especially during initial periods of exposure to the testing environment, and emit very few of the 22 kHz distress calls that are typically observed in males during fear learning or extinction paradigms. Overall, these findings show that female rodents display fear behavior repertoires divergent from males.
The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity in BLa. Cholinergic signaling in BLa has also been shown to modulate afferent glutamatergic inputs to this region. However, these studies, which have used cholinergic agonists or prolonged optogenetic stimulation of cholinergic fibers, may not reflect the effect of physiological acetylcholine release in the BLa. To better understand these effects of acetylcholine, we have used electrophysiology and optogenetics in male and female mouse brain slices to examine cholinergic regulation of afferent BLa input from cortex and midline thalamic nuclei (MTN). Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower muscarinic receptor (mAChR)-mediated depression. In contrast, at this same input, sustained ACh elevation through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission through mAChRs only. This suppression was not observed at MTN inputs to BLa. In agreement with this pathway-specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex (PL) than thalamus. Muscarinic inhibition at PL input required presynaptic M4 mAChRs, while at thalamic input it depended upon M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that is pathway specific and frequency dependent.Significance statement:Cholinergic modulation of the basolateral amygdala regulates formation of emotional memories, but the underlying mechanisms are not well understood. Here, we show, using mouse brain slices, that ACh differentially regulates afferent transmission to the BLa from cortex and MTN. Fast, phasic ACh release from a single optical stimulation biphasically regulates glutamatergic transmission at cortical inputs through nicotinic and muscarinic receptors, suggesting that cholinergic neuromodulation can serve precise, computational roles in the BLa. In contrast, sustained ACh elevation regulates cortical input through muscarinic receptors only. This muscarinic regulation is pathway specific with cortical input inhibited more strongly than MTN input. Specific targeting of these cholinergic receptors may thus provide a therapeutic strategy to bias amygdalar processing and regulate emotional memory.
The amygdalar anterior basolateral nucleus (BLa) plays a vital role in emotional behaviors. This region receives dense cholinergic projections from basal forebrain which are critical in regulating neuronal activity and synaptic transmission. Cholinergic signaling in BLa is thought to occur through both a slow mode of volume transmission as well as a rapid, phasic mode. However, the relative effect of each mode of signaling in BLa is not understood. Here, we used electrophysiology and optogenetics in mouse brain slices to compare regulation of afferent input from cortex and thalamus to the BLa by these two modes of transmission. Phasic ACh release evoked by single pulse stimulation of cholinergic terminals had a biphasic effect on glutamatergic transmission at cortical input, producing rapid nicotinic receptor-mediated facilitation followed by slower muscarinic receptor (mAChR)-mediated depression. In contrast, tonic elevation of ACh through application of the cholinesterase inhibitor physostigmine suppressed glutamatergic transmission at cortical inputs through mAChRs only. This suppression was not observed at thalamic inputs to BLa. In agreement with this pathway-specificity, the mAChR agonist, muscarine more potently suppressed transmission at inputs from prelimbic cortex (PL) than thalamus. Muscarinic inhibition at PL input was dependent on presynaptic M4 mAChRs, while at thalamic input it depended upon M3 mAChR-mediated stimulation of retrograde endocannabinoid signaling. Muscarinic inhibition at both pathways was frequency-dependent, allowing only high frequency activity to pass. These findings demonstrate complex cholinergic regulation of afferent input to BLa that depends upon the mode of ACh release and is both pathway specific and frequency dependent.
The cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre‐) littermates during fear learning, contextual and cue‐conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre‐ littermates, and displayed significant sex differences in contextual and cue‐conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre‐ rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses.
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