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A wide selection of behavioral assays in systems neuroscience relies on head-fixation protocols to integrate in vivo multi-photon imaging approaches. For this, simultaneous pupillometry and locomotion tracking in head-fixed mice are used to measure behavioral responses and identify neural correlates. Here, we present an open-source protocol for assembling a complete head-fixation system that integrates pupillometry and locomotion-estimated tracking with multi-photon calcium imaging. We include detailed procedures for head-fixation and for data collection., Competing Interests: Declaration of interests N.C.P. and J.R.-R. are co-founders of a company (Carolina Instruments, LLC) with a potential commercial interest in the technology presented in this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mentoring the next generation of neuroscientists from historically excluded backgrounds brings several challenges. Successful mentor-mentee relationships are critical for addressing these challenges. Rodriguez-Romaguera and Quirk reflect on lessons learned from their cross-racial mentor-mentee relationship that could apply to many mentors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Effectively assessing the realism and naturalness of images in virtual (VR) and augmented (AR) reality applications requires Full Reference Image Quality Assessment (FR-IQA) metrics that closely align with human perception. Deep learning-based IQAs that are trained on human-labeled data have recently shown promise in generic computer vision tasks. However, their performance decreases in applications where perfect matches between the reference and the distorted images should not be expected, or whenever distortion patterns are restricted to specific domains. Tackling this issue necessitates training a task-specific neural network, yet generating human-labeled FR-IQAs is costly, and deep learning typically demands substantial labeled data. To address these challenges, we developed ConIQA, a deep learning-based IQA that leverages consistency training and a novel data augmentation method to learn from both labeled and unlabeled data. This makes ConIQA well-suited for contexts with scarce labeled data. To validate ConIQA, we considered the example application of Computer-Generated Holography (CGH) where specific artifacts such as ringing, speckle, and quantization errors routinely occur, yet are not explicitly accounted for by existing IQAs. We developed a new dataset, HQA1k, that comprises 1000 natural images each paired with an image rendered using various popular CGH algorithms, and quality-rated by thirteen human participants. Our results show that ConIQA achieves superior Pearson (0.98), Spearman (0.965), and Kendall's tau (0.86) correlations over fifteen FR-IQA metrics by up to 5%, showcasing significant improvements in aligning with human perception on the HQA1k dataset., (© 2024. The Author(s).)

Traumatic social experiences redefine socially motivated behaviors to enhance safety and survival. Although many brain regions have been implicated in signaling a social threat, the mechanisms by which global neural networks regulate such motivated behaviors remain unclear. To address this issue, we first combined traditional and modern behavioral tracking techniques in mice to assess both approach and avoidance, as well as sub-second behavioral changes, during a social threat learning task. We were able to identify previously undescribed body and tail movements during social threat learning and recognition that demonstrate unique alterations into the behavioral structure of social motivation. We then utilized inter-regional correlation analysis of brain activity after a mouse recognizes a social threat to explore functional communication amongst brain regions implicated in social motivation. Broad brain activity changes were observed within the nucleus accumbens, the paraventricular thalamus, the ventromedial hypothalamus, and the nucleus of reuniens. Inter-regional correlation analysis revealed a reshaping of the functional connectivity across the brain when mice recognize a social threat. Altogether, these findings suggest that reshaping of functional brain connectivity may be necessary to alter the behavioral structure of social motivation when a social threat is encountered.

Social phobia is highly detrimental for social behavior, mental health, and productivity. Despite much previous research, the behavioral and neurobiological mechanisms associated with the development of social phobia remain elusive. To investigate these issues, the present study implemented a mouse model of social threat conditioning in which mice received electric shock punishment upon interactions with unfamiliar conspecifics. This resulted in immediate reductions in social behavior and robust increases in defensive mechanisms such as avoidance, freezing, darting, and ambivalent stretched posture. Furthermore, social deficits lasted for prolonged periods and were independent of contextual settings, sex variables, or particular identity of the social stimuli. Shedding new light into the neurobiological factors contributing to this phenomenon, we found that optogenetic silencing of the prelimbic (PL), but not the infralimbic (IL), subregion of the medial prefrontal cortex (mPFC) during training led to subsequent forgetting and development of lasting social phobia. Similarly, pharmacological inhibition of NMDARs in PL also impaired the development of social phobia. These findings are consistent with the notion that social-related trauma is a prominent risk factor for the development of social phobia, and that this phenomenon engages learning-related mechanisms within the prelimbic prefrontal cortex to promote prolonged representations of social threat.

Motivational states are regulated by complex networks across brain regions that are composed of genetically and functionally distinct neuronal populations. Disruption within these neural circuits leads to aberrant motivational states and are thought to be the root cause of psychiatric disorders related to reward processing and addiction. Critical technological advances in the field have revolutionized the study of neural systems by allowing the use of optical strategies to precisely control and visualize neural activity within genetically identified neural populations in the brain. This review will provide a brief introduction into the history of how technological advances in single-cell strategies have been applied to elucidate the neural circuits that underlie aberrant motivational states that often lead to dysfunction in reward processing and addiction., (Copyright © 2022 Cold Spring Harbor Laboratory Press; all rights reserved.)

Although autism spectrum disorder (ASD) is defined by impaired social communication and restricted and repetitive behaviors and interests, ASD is also characterized by impaired motivational processes. The "social motivation theory of autism" describes how social motivation disruptions in ASD in early childhood may impede the drive to engage in reciprocal social behaviors and ultimately interfere with the development of neural networks critical for social communication (Chevallier et al., Trends Cogn Sci 16:231-239, 2012b). Importantly, clinical studies and preclinical research using model organisms for ASD indicate that motivational impairments in ASD are not constrained to social rewards but are evident in response to a range of nonsocial rewards as well. Additionally, translational studies on certain genetically defined neurodevelopmental disorders associated with ASD indicate that these syndromic forms of ASD are also characterized by motivational deficits and mesolimbic dopamine impairments. In this chapter we summarize clinical and preclinical research relevant to reward processing impairments in ASD and related neurodevelopmental disorders. We also propose a nosology to describe reward processing impairments in these disorders that uses a three-axes model. In this triaxial nosology, the first axis defines the direction of the reward response (i.e., anhedonic, hyperhedonic); the second axis defines the construct of the reward process (e.g., reward liking, reward wanting); and the third axis defines the context of the reward response (e.g., social, nonsocial). A more precise nosology for describing reward processing impairments in ASD and related neurodevelopmental disorders will aid in the translation of preclinical research to clinical investigations which will ultimately help to speed up the development of interventions that target motivational systems for ASD and related neurodevelopmental disorders., (© 2022. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Over the past few decades, the bed nucleus of the stria terminalis (BNST) gained popularity as a unique brain region involved in regulating motivated behaviors related to neuropsychiatric disorders. The BNST, a component of the extended amygdala, consists of a variety of subnuclei and neuronal ensembles. Multiple studies have highlighted the BNST as playing a fundamental role in integrating information by interfacing with other brain regions to regulate distinct aspects of motivated behaviors associated with stress, anxiety, depression, and decision-making. However, due to the high molecular heterogeneity found within BNST neurons, the precise mechanisms by which this region regulates distinct motivational states remains largely unclear. Single-cell RNA sequencing data have revealed that the BNST consists of multiple genetically identifiable cell-type clusters. Contemporary tools can therefore be leveraged to target and study such cell-types and elucidate their precise functional role. In this review, we discuss the different subsets of neurons found in the BNST, their anatomical distribution, and what is currently known about BNST cell-types in regulating motivated behaviors., (Published by Elsevier B.V.)

Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (Pnoc BNST ) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that Pnoc BNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in Pnoc BNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that Pnoc BNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism, Shank3b knock-out (KO) mice. Male Shank3b KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses. SIGNIFICANCE STATEMENT Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist., (Copyright © 2020 the authors.)

The paraventricular thalamus (PVT) is an interface for brain reward circuits, with input signals arising from structures, such as prefrontal cortex and hypothalamus, that are broadcast to downstream limbic targets. However, the precise synaptic connectivity, activity, and function of PVT circuitry for reward processing are unclear. Here, using in vivo two-photon calcium imaging, we find that PVT neurons projecting to the nucleus accumbens (PVT-NAc) develop inhibitory responses to reward-predictive cues coding for both cue-reward associative information and behavior. The multiplexed activity in PVT-NAc neurons is directed by opposing activity patterns in prefrontal and lateral hypothalamic afferent axons. Further, we find that prefrontal cue encoding may maintain accurate cue-reward processing, as optogenetic disruption of this encoding induced long-lasting effects on downstream PVT-NAc cue responses and behavioral cue discrimination. Together, these data reveal that PVT-NAc neurons act as an interface for reward processing by integrating relevant inputs to accurately inform reward-seeking behavior., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue-reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue-reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue-reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue-reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue-reward associative memory to support behavioral adaptation.

Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses., Competing Interests: MD, CB, JR, PP, AB, CR, GQ No competing interests declared, (© 2018, Diehl et al.)

Social isolation is a stressful condition that often leads to maladaptive behaviors. In this issue of Cell, Zelikowsky et al. find that chronic social isolation stress triggers an increase in neuronal tachykinin signaling across distinct brain regions that mediate fear and aggression, elucidating the neural basis of these maladaptive responses., (Copyright © 2018. Published by Elsevier Inc.)

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data., Competing Interests: PZ, SR, JR, JJ, SN, AG, JF, EP, GS, RH, MK, BS, RK, LP No competing interests declared, (© 2018, Zhou et al.)

Background: Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VS) as a possible treatment for drug addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine whether DBS of the VS could facilitate the extinction of morphine-induced conditioned place preference in rats., Methods: Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine conditioned place preference. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high- (130 Hz) or low- (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug-seeking behaviors., Results: High-frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high-frequency DBS of the ventral-VS had no effect. In contrast, low-frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low-frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala., Conclusions: Our results suggest that low-frequency (rather than high-frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addiction., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The habenula is a tiny brain region the size of a pea in humans. This region is highly conserved across vertebrates and has been traditionally overlooked by neuroscientists. The name habenula is derived from the Latin word habena, meaning "little rein", because of its elongated shape. Originally its function was thought to be related to the regulation of the nearby pineal gland (which Rene Descartes described as the "principal seat of the soul"). More recent evidence, however, demonstrates that the habenula acts as a critical neuroanatomical hub that connects and regulates brain regions important for divergent motivational states and cognition. In this Primer, we will discuss the recent and converging evidence that points to the habenula as a key brain region for motivation and decision-making., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Understanding the neural mechanisms of psychiatric disorders requires the use of rodent models; however, frontal-striatal homologies between rodents and primates are unclear. In contrast, within the striatum, the shell of the nucleus accumbens, the hippocampal projection zone, and the amygdala projection zone (referred to as the striatal emotion processing network [EPN]) are conserved across species. We used the relationship between the EPN and projections from the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) to assess network similarities across rats and monkeys., Methods: We first compared the location and extent of each major component of the EPN in rats and macaques. Next, we used anatomic cases with anterograde injections in ACC/OFC to determine the extent to which corticostriatal terminal fields overlapped with these components and with each other., Results: The location and size of each component of the EPN were similar across species, containing projections primarily from infralimbic cortex in rats and area 25 in monkeys. Other ACC/OFC terminals overlapped extensively with infralimbic cortex/area 25 projections, supporting cross-species similarities in OFC topography. However, dorsal ACC had different connectivity profiles across species. These results were used to segment the monkey and rat striata according to ACC/OFC inputs., Conclusions: Based on connectivity with the EPN, and consistent with prior literature, the infralimbic cortex and area 25 are likely homologues. We also see evidence of OFC homologies. Along with segmenting the striatum and identifying striatal hubs of overlapping inputs, these results help to translate findings between rodent models and human pathology., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients' response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder., Methods: Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance., Results: Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP., Conclusions: DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients' response to ERP therapy., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519-11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models., (Copyright © 2015 the American Physiological Society.)

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces anxiety, fear, and compulsive symptoms in patients suffering from refractory obsessive-compulsive disorder. In a rodent model, DBS-like high-frequency stimulation of VS can either enhance or impair extinction of conditioned fear, depending on the location of electrodes within VS (dorsal vs ventral). As striatal DBS activates fibers descending from the cortex, we reasoned that the differing effects on extinction may reflect differences in cortical sources of fibers passing through dorsal-VS and ventral-VS. In agreement with prior anatomical studies, we found that infralimbic (IL) and anterior insular (AI) cortices project densely through ventral-VS, the site where DBS impaired extinction. Contrary to IL and AI, we found that medial orbitofrontal cortex (mOFC) projects densely through dorsal-VS, the site where DBS enhanced extinction. Furthermore, pharmacological inactivation of mOFC reduced conditioned fear and DBS of dorsal-VS-induced plasticity (pERK) in mOFC neurons. Our results support the idea that VS DBS modulates fear extinction by stimulating specific fibers descending from mOFC and prefrontal cortices.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD.

Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC., (© 2010 Blackwell Publishing Ltd.)

Background: Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing., Methods: One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed., Results: Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons., Conclusion: Propranolol reduced the expression of conditioned fear, without interfering with extinction learning. Reduced fear with intact extinction suggests a possible use for propranolol in reducing anxiety during extinction-based exposure therapies, without interfering with long-term clinical response.