Perirhinal damage produces modality-dependent deficits in fear learning.

The perirhinal cortex (PER) receives multimodal and unimodal sensory information from all modalities. In addition, the PER is anatomically connected with several brain regions that support fear learning. Several studies suggest that the PER is involved in fear conditioning to discontinuous auditory cues but not to continuous auditory cues. To date, studies examining the role of the PER in fear conditioning has largely focused on auditory and contextual stimuli. The present study assessed whether the role of the PER in fear conditioning would extend to visual modalities. Rodents were randomly assigned to one of four conditioned stimuli, which consisted of either a tone or a light stimulus that was either continuous or discontinuous. Pre-training excitotoxic lesions to the PER significantly reduced freezing to auditory and visual cues during the acquisition phase regardless of stimulus continuity. During subsequent testing, perirhinal lesions produced significant decreases in freezing levels to both continuous and discontinuous tones but not to either of the light CS groups. These results suggest that the PER is involved in the acquisition of fear across multiple cue modalities. However, the PER may have a more limited role in the retrieval of the fear memory dependent upon the cue modality.

Perirhinal cortex inactivation produces retrieval deficits in fear extinction to a discontinuous visual stimulus.

Several studies suggest that the perirhinal cortex (PER) may function to unitize stimulus components across time or modalities. While the PER has been shown to be critical for fear acquisition to discontinuous stimuli, the role of the PER in fear extinction memory has not been evaluated. The current study assessed the involvement of the PER during fear extinction training to a continuous or discontinuous conditioned stimulus (CS). Rats were randomly assigned to 1 of 4 groups based on 2 factors: the CS type (a continuous or discontinuous light) and a pretesting PER manipulation (muscimol inactivation or saline). Results showed that PER inactivation impaired fear memory to both CS types; however, PER inactivation had only impaired extinction memory to the discontinuous light. These results suggest the role of the PER in stimulus unitization extends to supporting the acquisition of fear extinction memory. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Instantaneous amplitude and shape of postrhinal theta oscillations differentially encode running speed.

Hippocampal theta oscillations have a temporally asymmetric waveform shape, but it is not known if this theta asymmetry extends to all other cortical regions involved in spatial navigation and memory. Here, using both established and improved cycle-by-cycle analysis methods, we show that theta waveforms in the postrhinal cortex are also temporally asymmetric. On average, the falling phase of postrhinal theta cycles lasts longer than the subsequent rising phase. There are, however, rapid changes in both the instantaneous amplitude and instantaneous temporal asymmetry of postrhinal theta cycles. These rapid changes in amplitude and asymmetry are very poorly correlated, indicative of a mechanistic disconnect between these theta cycle features. We show that the instantaneous amplitude and asymmetry of postrhinal theta cycles differentially encode running speed. Although theta amplitude continues to increase at the fastest running speeds, temporal asymmetry of the theta waveform shape plateaus after medium speeds. Our results suggest that the amplitude and waveform shape of individual postrhinal theta cycles may be governed by partially independent mechanisms and emphasize the importance of employing a single cycle approach to understanding the genesis and behavioral correlates of cortical theta rhythms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Revisiting the autoconditioning hypothesis for acquired reactivity to ultrasonic alarm calls.

Rats emit 22 kHz ultrasonic vocalizations (USVs) in association with pain, fear, or distress. Whereas the capacity to produce USVs is innate, reactivity to them appears to require experience. Specifically, 22 kHz USVs fail to elicit freezing behavior in naïve laboratory rats. However, these "alarm calls" do elicit freezing in rats that previously experienced foot shocks. These findings led to the hypothesis that acquired reactivity is based on "autoconditioning"-learning in which self-generated 22 kHz USVs serve as Pavlovian cues that become associated with foot shocks. The current study tested the autoconditioning hypothesis by devocalizing rats through a unilateral transection of the recurrent laryngeal nerve (Experimental group). Subsequently, animals in both the Experimental and sham-operated Control groups received five unsignaled foot shocks. One or two days later, both groups were tested for USV-elicited freezing in a novel context. Recurrent laryngeal nerve transection failed to prevent or even diminish USV-elicited freezing. In fact, both groups showed large and comparable increases in freezing to USV presentations. A subset of Control animals failed to vocalize during conditioning, while some Experimental animals did vocalize during conditioning. Animals were therefore re-grouped and reanalyzed based on whether they vocalized during conditioning. Again, both groups showed large and comparable increases in USV-elicited freezing. These results disconfirm the essential tenet or prediction of the autoconditioning hypothesis. Alternative mechanisms for acquired reactivity to 22 kHz USVs are therefore considered.

Functional connectivity of dorsal and ventral frontoparietal seed regions during auditory orienting.

Our ability to refocus auditory attention is vital for even the most routine day-to-day activities. Shifts in auditory attention can be initiated "voluntarily," or triggered "involuntarily" by unexpected novel sound events. Here we employed psychophysiological interaction (PPI) analyses of auditory functional MRI data, to compare functional connectivity patterns of distinct frontoparietal cortex regions during cued voluntary vs. novelty-driven involuntary auditory attention shifting. Overall, our frontoparietal seed regions exhibited significant PPI increases with auditory cortex (AC) areas during both cued and novelty-driven orienting. However, significant positive PPI patterns associated with voluntary auditory attention (cue>novel task regressor), but mostly absent in analyses emphasizing involuntary orienting (novel>cue task regressor), were observed with seeds within the frontal eye fields (FEF), superior parietal lobule (SPL), and right supramarginal gyri (SMG). In contrast, significant positive PPIs associated selectively with involuntary orienting were observed between ACs and seeds within the bilateral anterior interior frontal gyri (IFG), left posterior IFG, SMG, and posterior cingulate cortices (PCC). We also found indices of lateralization of different attention networks: PPI increases selective to voluntary attention occurred primarily within right-hemispheric regions, whereas those related to involuntary orienting were more frequent with left-hemisphere seeds. In conclusion, despite certain similarities in PPI patterns across conditions, the more dorsal aspects of right frontoparietal cortex demonstrated wider connectivity during cued/voluntary attention shifting, whereas certain left ventral frontoparietal seeds were more widely connected during novelty-triggered/involuntary orienting. Our findings provide partial support for distinct attention networks for voluntary and involuntary auditory attention.

Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit.

IMPORTANCE: Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population. OBJECTIVE: To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD. DESIGN: Cross-sectional, case-control, functional magnetic resonance imaging study. SETTING: Academic medical center. PARTICIPANTS: Twenty-one patients with OCD and 21 healthy participants. MAIN OUTCOMES AND MEASURES: Skin conductance responses and blood oxygenation level-dependent responses. RESULTS: The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity. CONCLUSIONS AND RELEVANCE: As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD.

Single neuron activity and theta modulation in postrhinal cortex during visual object discrimination.

Postrhinal cortex, rodent homolog of the primate parahippocampal cortex, processes spatial and contextual information. Our hypothesis of postrhinal function is that it serves to encode context, in part, by forming representations that link objects to places. To test this hypothesis, we recorded postrhinal neurons and local field potentials (LFPs) in rats trained on a two-choice, visual discrimination task. As predicted, many postrhinal neurons signaled object-location conjunctions. Another large proportion encoded egocentric motor responses. In addition, postrhinal LFPs exhibited strong oscillatory rhythms in the theta band, and many postrhinal neurons were phase locked to theta. Although correlated with running speed, theta power was lower than predicted by speed alone immediately before and after choice. However, theta power was significantly increased following incorrect decisions, suggesting a role in signaling error. These findings provide evidence that postrhinal cortex encodes representations that link objects to places and suggest postrhinal theta modulation extends to cognitive as well as spatial functions.

Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit.

OBJECTIVE: Individual differences in a person's ability to control fear have been linked to activation in the dorsal anterior cingulate cortex, the ventromedial prefrontal cortex, and the amygdala. This study investigated whether functional variance in this network can be predicted by resting metabolism in these same regions. METHOD: The authors measured resting brain metabolism in healthy volunteers with positron emission tomography using [18F]fluorodeoxyglucose. This was followed by a 2-day fear conditioning and extinction training paradigm using functional MRI to measure brain activation during fear extinction and recall. The authors used skin conductance response to index conditioned responding, and they used resting metabolism in the amygdala, the dorsal anterior cingulate cortex, and the ventromedial prefrontal cortex to predict responses during fear extinction and extinction recall. RESULTS: During extinction training, resting amygdala metabolism positively predicted activation in the ventromedial prefrontal cortex and negatively predicted activation in the dorsal anterior cingulate cortex. In contrast, during extinction recall, resting amygdala metabolism negatively predicted activation in the ventromedial prefrontal cortex and positively predicted activation in the dorsal anterior cingulate cortex. In addition, resting metabolism in the dorsal anterior cingulate cortex predicted fear expression (as measured by skin conductance response) during extinction recall. CONCLUSIONS: Resting brain metabolism predicted neuronal reactivity and skin conductance changes associated with the recall of the fear extinction memory.

Aging-related changes in calcium-binding proteins in rat perirhinal cortex.

Dysregulation of intracellular calcium homeostasis has been linked to neuropathological symptoms observed in aging and age-related disease. Alterations in the distribution and relative frequency of calcium-binding proteins (CaBPs), which are important in regulating intracellular calcium levels, may contribute to disruption of calcium homeostasis. Here we examined the laminar distribution of three CaBPs in rat perirhinal cortex (PR) as a function of aging. Calbindin-D28k (CB), parvalbumin (PV), and calretinin (CR) were compared in adult (4 mo.), middle-aged (13 mo.) and aged (26 mo.) rats. Results show an aging-related and layer-specific decrease in the number of CB-immunoreactive (-ir) neurons, beginning in middle-aged animals. Dual labeling suggests that the age-related decrease in CB reflects a decrease in neurons that are not immunoreactive for the inhibitory neurotransmitter GABA. In contrast, no aging-related differences in PV- or CR-immunoreactivity were observed. These data suggest that selective alterations in CB-ir neurons may contribute to aging-related learning and memory deficits in tasks that depend upon PR circuitry.

The Floor Projection Maze: A novel behavioral apparatus for presenting visual stimuli to rats.

There is a long tradition of studying visual learning in rats by presenting stimuli vertically on cards or monitors. The procedures are often labor intensive and the rate of acquisition can be prohibitively low. Available evidence suggests that rats process visual information presented in the lower visual hemifield more effectively than information presented in the upper visual hemifield. We capitalized on these findings by developing a novel apparatus, the Floor Projection Maze, for presenting visual information directly to the floor of an exploratory maze. Two-dimensional (2D) visual stimuli were presented on the floor by back-projecting an image from a standard digital projector to the semi-transparent underside of the floor of an open maze. Long-Evans rats rapidly acquired easy 2D visual discriminations (Experiment 1). Rats were also able to learn a more difficult shape discrimination in dramatically fewer trials than previously reported for the same discrimination when presented vertically (Experiment 2). The two choice discrimination task was adapted to determine contrast sensitivity thresholds in a naïve group of rats (Experiment 3). Contrast sensitivity thresholds were uniform across three subjects, demonstrating that the Floor Projection Maze can be used for visual psychophysics in rats. Our findings demonstrate that rats can rapidly acquire visual tasks when stimuli are presented horizontally on the floor, suggesting that this novel behavioral apparatus will provide a powerful behavioral paradigm in the future.

Recognition memory: can you teach an old dogma new tricks?

Familiarity and recollection are components of recognition memory. Whether these underlie two separate processes or a single process differing only in memory strength is a matter of continued debate. In this issue of Neuron, Haskins et al. provide further evidence in support of a dual-process perspective, whereas Shrager et al. provide evidence supporting a single-process viewpoint.

Single-unit firing in rat perirhinal cortex caused by fear conditioning to arbitrary and ecological stimuli.

Pretraining lesions of rat perirhinal cortex (PR) severely impair pavlovian fear conditioning to a 22 kHz ultrasonic vocalization (USV) cue. However, PR lesions are without significant effect when the cue is a continuous tone at the same or a lower frequency. Here we examined fear-conditioning-produced changes in single-unit firing elicited in rat PR by a 22 kHz tone cue or a 22 kHz USV cue. Chronic recording electrodes were introduced from the lateral surface of the skull. Altogether, 200 well isolated units were studied in 28 rats. Overall, 73% of the recorded single units (145 of 200 units) evidenced statistically significant firing changes in response to the tone or USV conditional stimulus (CS) after it had been paired several times with an aversive unconditional stimulus (US). Interestingly, 33% of units (66 of 200 units) that were initially CS-unresponsive became CS-responsive after conditioning. After conditioning, there were two notable differences between single-unit responses elicited by the USV cue and those elicited by the tone cue. First, 11% of the units (14 of 123 units) recorded from the USV-conditioned group displayed a precisely timed increase in firing rate during the 260 ms interval in which the US had previously occurred. This US-timed response was unique to the USV-conditioned group. Second, the mean latency of cue-elicited firing was approximately 30 ms longer in the USV-conditioned group than in the tone-conditioned group. These cue-specific differences in acquired firing latencies and acquired firing patterns suggest that spectrotemporal properties of a CS can control the essential circuitry or neurophysiological mechanisms underlying fear conditioning.

Functional neuroanatomy of the parahippocampal region: the lateral and medial entorhinal areas.

The entorhinal cortex (EC) serves a pivotal role in corticohippocampal interactions, but a complete description of its extrinsic connections has not been presented. Here, we have summarized the cortical, subcortical, and hippocampal connections of the lateral entorhinal area (LEA) and the medial entorhinal area (MEA) in the rat. We found that the targets and relative strengths of the entorhinal connections are strikingly different for the LEA and MEA. For example, the LEA receives considerably heavier input from the piriform and insular cortices, whereas the MEA is more heavily targeted by the visual, posterior parietal, and retrosplenial cortices. Regarding subcortical connections, the LEA receives heavy input from the amygdala and olfactory structures, whereas the MEA is targeted by the dorsal thalamus, primarily the midline nuclei and also the dorsolateral and dorsoanterior thalamic nuclei. Differences in the LEA and MEA connections with hippocampal and parahippocampal structures are also described. In addition, because the EC is characterized by bands of intrinsic connectivity that span the LEA and MEA and project to different septotemporal levels of the dentate gyrus, special attention was paid to the efferents and afferents of those bands. Finally, we summarized the connections of the dorsocaudal MEA, the region in which the entorhinal "grid cells" were discovered. The subregional differences in entorhinal connectivity described here provide further evidence for functional diversity within the EC. It is hoped that these findings will inform future studies of the role of the EC in learning and memory.

Functional neuroanatomy of the parahippocampal region in the rat: the perirhinal and postrhinal cortices.

The parahippocampal region in the rodent brain includes the perirhinal, postrhinal, and entorhinal cortices, the presubiculum, and the parasubiculum. In recent years, the perirhinal and postrhinal cortices have been a focus in memory research because they supply highly processed, polymodal sensory information to the hippocampus, both directly and via the entorhinal cortex. Available evidence indicates that these cortices receive different complements of cortical information, which are then forwarded to the hippocampus via parallel pathways. Here we have summarized the cortical, subcortical, and hippocampal connections of the perirhinal and postrhinal cortices in order to provide further insight into the nature of the information that is processed by these regions prior to arriving in the hippocampus. As has been previously described, the cortical afferents of the rodent postrhinal cortex are dominated by structures known to be involved in the processing of visual and spatial information, whereas the cortical afferents of the perirhinal cortex result in remarkable convergence of polymodal sensory information. The two regions are also differentiated by their cortical efferents. The perirhinal cortex projects more strongly to piriform, frontal, and insular regions, whereas the postrhinal cortex projects preferentially to visual and visuospatial regions. The subcortical connections of the two regions provide further evidence that they have different functions. For example, the perirhinal cortex has strong reciprocal connections with the amygdala, which suggest involvement in processing affective stimuli. Subcortical input to the postrhinal cortex is dominated by projections from dorsal thalamic structures, particularly the lateral posterior nucleus. Although the perirhinal and postrhinal cortices are considered to contribute to the episodic memory system, many questions remain about their particular roles. A detailed description of the anatomical connections of the perirhinal and postrhinal cortices will permit the generation of new, anatomically guided, hypotheses about their role in episodic memory and other cognitive processes.