Sharon C. Furtak

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.

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

OBJECTIVE Individual differences in a persons 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.

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.

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 ∼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.

Morphology and ontogeny of rat perirhinal cortical neurons

Golgi‐impregnated neurons from rat perirhinal cortex (PR) were classified into one of 15 distinct morphological categories (N = 6,891). The frequency of neurons in each cell class was determined as a function of the layer of PR and the age of the animal, which ranged from postnatal day 0 (P0) to young adulthood (P45). The developmental appearance of Golgi‐impregnated neurons conformed to the expected “inside‐out” pattern of development, meaning that cells populated in deep before superficial layers of PR. The relative frequencies of different cell types changed during the first 2 weeks of postnatal development. The largest cells, which were pyramidal and spiny multipolar neurons, appeared earliest. Aspiny stellate neurons were the last to appear. The total number of Golgi‐impregnated neurons peaked at P10–12, corresponding to the time of eye‐opening. This early increase in the number of impregnated neurons parallels observations in other cortical areas. The relative frequency of the 15 cell types remained constant between P14 to P45. The proportion of pyramidal neurons in PR (≈50%) was much smaller than is typical of neocortex (≈70%). A correspondingly larger proportion of PR neurons were nonpyramidal cells that are less common in neocortex. The relative frequency distribution of cell types creates an overall impression of considerable morphological diversity, which is arguably related to the particular manner in which this periallocortical brain region processes and stores information. J. Comp. Neurol. 505:493–510, 2007.

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.