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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.)

Background: Individuals with obsessive-compulsive disorder (OCD) show persistent avoidance behaviors, often in the absence of actual threat. Quality-of-life costs and heterogeneity support the need for novel brain-behavior intervention targets. Informed by mechanistic and anatomical studies of persistent avoidance in rodents and nonhuman primates, our goal was to test whether connections within a hypothesized persistent avoidance-related network predicted OCD-related harm avoidance (HA), a trait measure of persistent avoidance. We hypothesized that 1) HA, not an OCD diagnosis, would be associated with altered endogenous connectivity in at least one connection in the network; 2) HA-specific findings would be robust to comorbid symptoms; and 3) reliable findings would replicate in a holdout testing subsample., Methods: Using resting-state functional connectivity magnetic resonance imaging, cross-validated elastic net for feature selection, and Poisson generalized linear models, we tested which connections significantly predicted HA in our training subsample (n = 73; 71.8% female; healthy control group n = 36, OCD group n = 37); robustness to comorbidities; and replicability in a testing subsample (n = 30; 56.7% female; healthy control group n = 15, OCD group n = 15)., Results: Stronger inverse connectivity between the right dorsal anterior cingulate cortex and right basolateral amygdala and stronger positive connectivity between the right ventral anterior insula and left ventral striatum were associated with greater HA across groups. Network connections did not discriminate OCD diagnostic status or predict HA-correlated traits, suggesting sensitivity to trait HA. The dorsal anterior cingulate cortex-basolateral amygdala relationship was robust to controlling for comorbidities and medication in individuals with OCD and was also predictive of HA in our testing subsample., Conclusions: Stronger inverse dorsal anterior cingulate cortex-basolateral amygdala connectivity was robustly and reliably associated with HA across groups and in OCD. Results support the relevance of a cross-species persistent avoidance-related network to OCD, with implications for precision-based approaches and treatment., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: A common symptom of obsessive-compulsive disorder is the persistent avoidance of cues incorrectly associated with negative outcomes. This maladaptation becomes increasingly evident as subjects fail to respond to extinction-based treatments such as exposure-with-response prevention therapy. While previous studies have highlighted the role of the insular-orbital cortex in fine-tuning avoidance-based decisions, little is known about the projections from this area that might modulate compulsive-like avoidance., Methods: Here, we used anatomical tract-tracing, single-unit recording, and optogenetics to characterize the projections from the insular-orbital cortex. To model exposure-with-response prevention and persistent avoidance in rats, we used the platform-mediated avoidance task followed by extinction-with-response prevention training., Results: Using tract-tracing and unit recording, we found that projections from the agranular insular/lateral orbital (AI/LO) cortex to the prefrontal cortex predominantly target the rostral portion of the prelimbic (rPL) cortex and excite rPL neurons. Photoinhibiting this projection induced persistent avoidance after extinction-with-response prevention training, an effect that was still present 1 week later. Consistent with this, photoexcitation of this projection prevented persistent avoidance in overtrained rats. This projection to rPL appears to be key for AI/LO's effects, considering that there was no effect of photoinhibiting AI/LO projections to the ventral striatum or basolateral amygdala., Conclusions: Our findings suggest that projections from the AI/LO to the rPL decreases the likelihood of avoidance behavior following extinction. In humans, this connectivity may share some homology of projections from lateral prefrontal cortices (i.e., ventrolateral prefrontal cortex, orbitofrontal cortex, and insula) to other prefrontal areas and the anterior cingulate cortex, suggesting that reduced activity in these pathways may contribute to obsessive-compulsive disorder., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The long-lasting nature of fear memories is essential for survival, but the neural circuitry for retrieval of these associations changes with the passage of time. We previously reported a time-dependent shift from prefrontal-amygdalar circuits to prefrontal-thalamic circuits for the retrieval of auditory fear conditioning. However, little is known about the time-dependent changes in the originating site, the prefrontal cortex. Here we monitored the responses of prelimbic (PL) prefrontal neurons to conditioned tones at early (2 h) vs. late (4 days) timepoints following training. Using c-Fos, we find that PL neurons projecting to the amygdala are activated early after learning, but not later, whereas PL neurons projecting to the paraventricular thalamus (PVT) show the opposite pattern. Using unit recording, we find that PL neurons in layer V (the origin of projections to amygdala) showed cue-induced excitation at earlier but not later timepoints, whereas PL neurons in Layer VI (the origin of projections to PVT) showed cue-induced inhibition at later, but not earlier, timepoints, along with an increase in spontaneous firing rate. Thus, soon after conditioning, there are conditioned excitatory responses in PL layer V which influence the amygdala. With the passage of time, however, retrieval of fear memories shifts to inhibitory responses in PL layer VI which influence the midline thalamus., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quiñones-Laracuente, Vega-Medina and Quirk.)

The ability of animals to maximize benefits and minimize costs during approach-avoidance conflicts is an important evolutionary tool, but little is known about the emergence of specific strategies for conflict resolution. Accordingly, we developed a simple approach-avoidance conflict task in rats that pits the motivation to press a lever for sucrose against the motivation to step onto a distant platform to avoid a footshock delivered at the end of a 30 s tone (sucrose is available only during the tone). Rats received conflict training for 16 days to give them a chance to optimize their strategy by learning to properly time the expression of both behaviors across the tone. Rats unexpectedly separated into three distinct subgroups: those pressing early in the tone and avoiding later (Timers, 49%); those avoiding throughout the tone (Avoidance-preferring, 32%); and those pressing throughout the tone (Approach-preferring, 19%). The immediate early gene cFos revealed that Timers showed increased activity in the ventral striatum and midline thalamus relative to the other two subgroups, Avoidance-preferring rats showed increased activity in the amygdala, and Approach-preferring rats showed decreased activity in the prefrontal cortex. This pattern is consistent with low fear and high behavioral flexibility in Timers, suggesting the potential of this task to reveal the neural mechanisms of conflict resolution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bravo-Rivera, Rubio Arzola, Caban-Murillo, Vélez-Avilés, Ayala-Rosario and Quirk.)

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the "workforce") and the harnessing of the heterogeneity of thought (the "thinkforce") to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success.

The prefrontal cortex (PFC) integrates incoming information to guide our actions. When motivation for food-seeking competes with avoidance of danger, the PFC likely plays a role in selecting the optimal choice. In platform-mediated active avoidance, rats avoid a tone-signaled footshock by stepping onto a nearby platform, delaying access to sucrose pellets. This avoidance requires prelimbic (PL) PFC, basolateral amygdala (BLA), and ventral striatum (VS). We previously showed that inhibitory tone responses of PL neurons correlate with avoidability of shock (Diehl et al., 2018). Here, we optogenetically modulated PL terminals in VS and BLA to identify PL outputs regulating avoidance. Photoactivating PL-VS projections reduced avoidance, whereas photoactivating PL-BLA projections increased avoidance. Moreover, photosilencing PL-BLA or BLA-VS projections reduced avoidance, suggesting that VS receives opposing inputs from PL and BLA. Bidirectional modulation of avoidance by PL projections to VS and BLA enables the animal to make appropriate decisions when faced with competing drives., Competing Interests: MD, JI, JM, GR, FG, VV, GQ No competing interests declared, (© 2020, Diehl et al.)

Obsessive-compulsive disorder (OCD) is characterized by compulsive behaviors that often resemble avoidance of perceived danger. OCD can be treated with exposure-with-response prevention (ERP) therapy in which patients are exposed to triggers but are encouraged to refrain from compulsions, to extinguish compulsive responses. The compulsions of OCD are strengthened by many repeated exposures to triggers, but little is known about the effects of extended repetition of avoidance behaviors on extinction. Here we assessed the extent to which overtraining of active avoidance affects subsequent extinction-with-response prevention (Ext-RP) as a rodent model of ERP, in which rats are extinguished to triggers, while the avoidance option is prevented. Male rats conditioned for 8d or 20d produced similar avoidance behavior to a tone paired with a shock, however, the 20d group showed a severe impairment of extinction during Ext-RP, as well as heightened anxiety. Furthermore, the majority of overtrained (20d) rats (75%) exhibited persistent avoidance following Ext-RP. In the 8d group, only a minority of rats (37%) exhibited persistent avoidance, and this was associated with elevated activity (c-Fos) in the prelimbic cortex and nucleus accumbens. In the 20d group, the minority of non-persistent rats (25%) showed elevated activity in the insular-orbital cortex and paraventricular thalamus. Lastly, extending the duration of Ext-RP prevented the deleterious effects of overtraining on extinction and avoidance. These rodent findings suggest that repeated expression of compulsion-like behaviors biases individuals toward persistent avoidance and alters avoidance circuits, thereby reducing the effectiveness of current extinction-based therapies.

Adult mammalian brains have largely lost neuroregeneration capability except for a few niches. Previous studies have converted glial cells into neurons, but the total number of neurons generated is limited and the therapeutic potential is unclear. Here, we demonstrate that NeuroD1-mediated in situ astrocyte-to-neuron conversion can regenerate a large number of functional new neurons after ischemic injury. Specifically, using NeuroD1 adeno-associated virus (AAV)-based gene therapy, we were able to regenerate one third of the total lost neurons caused by ischemic injury and simultaneously protect another one third of injured neurons, leading to a significant neuronal recovery. RNA sequencing and immunostaining confirmed neuronal recovery after cell conversion at both the mRNA level and protein level. Brain slice recordings found that the astrocyte-converted neurons showed robust action potentials and synaptic responses at 2 months after NeuroD1 expression. Anterograde and retrograde tracing revealed long-range axonal projections from astrocyte-converted neurons to their target regions in a time-dependent manner. Behavioral analyses showed a significant improvement of both motor and cognitive functions after cell conversion. Together, these results demonstrate that in vivo cell conversion technology through NeuroD1-based gene therapy can regenerate a large number of functional new neurons to restore lost neuronal functions after injury., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obsessive-Compulsive Disorder (OCD) is characterized by repetitive avoidance behavior which is distressing and associated with marked impairment of everyday life. Recently, paradigms have been designed to explore the hypothesis that avoidance behavior in OCD is consistent with a formal conception of habit. Such studies have involved a devaluation paradigm, in which the value of a previously rewarded cue is altered so that avoidance is no longer necessary. We employed a rule-based avoidance task which included a devaluation, examining behavioral performance on the task and their neural correlates using functional MRI in groups of participants with OCD (n = 44) and healthy control participants (n = 46). Neuroimaging data were analyzed using a general linear model (GLM), modelling valued, devalued and control cues, as well as feedback events. First, while no overall effect of OCD was seen on devaluation performance, patients with longer illness duration showed poorer devaluation performance (χ 2  = 13.84, p < 0.001). Reduced devaluation was related to impaired learning on the overtraining phase of the task, and to enhanced feedback activation in the caudate and parietal lobe during within-scanner retraining (T = 5.52, p&#95;FWE = 0.003), across all participants. Second, a significant interaction effect was observed in the premotor cortex (F = 29.03, p&#95;FWE = 0.007) coupled to the devalued cue. Activations were divergent in participants with OCD (lower activation) and healthy controls (higher activation) who did not change responding to the devalued cue following devaluation, and intermediate in participants who did change responding (T = 5.39, p&#95;FWE = 0.003). Finally, consistent with previous work, medial orbitofrontal cortex activation coupled to valued cues was reduced in OCD compared to controls (T = 3.49, p&#95;FWE = 0.009). The findings are discussed in terms of a prediction error-based model of goal-directed and habitual control: specifically, how goal-directed control might be diminished in OCD in favor of habits. They suggest that illness duration might be significant determinant of variation in impaired goal-directed learning in OCD, and be a factor relevant for understanding discrepancies across studies. Overall, the study shows the potential of conceptual replication attempts to provide complementary insights into compulsive behavior and its associated neural circuitry in OCD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Traditional active avoidance tasks have advanced the field of aversive learning and memory for decades and are useful for studying simple avoidance responses in isolation; however, these tasks have limited clinical relevance because they do not model several key features of clinical avoidance. In contrast, platform-mediated avoidance (PMA) more closely resembles clinical avoidance because the response i) is associated with an unambiguous safe location, ii) is not associated with an artificial termination of the warning signal, and iii) is associated with a decision-based appetitive cost. Recent findings on the neuronal circuits of PMA have confirmed that amygdala-striatal circuits are essential for avoidance. In PMA, however, the prelimbic cortex facilitates the avoidance response early during the warning signal, perhaps through disinhibition of the striatum. Future studies on avoidance should account for additional factors such as sex differences and social interactions that will advance our understanding of maladaptive avoidance contributing to neuropsychiatric disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Active communication between researchers and society is necessary for the scientific community's involvement in developing science-based policies. This need is recognized by governmental and funding agencies that compel scientists to increase their public engagement and disseminate research findings in an accessible fashion. Storytelling techniques can help convey science by engaging people's imagination and emotions. Yet, many researchers are uncertain about how to approach scientific storytelling, or feel they lack the tools to undertake it. Here we explore some of the techniques intrinsic to crafting scientific narratives, as well as the reasons why scientific storytelling may be an optimal way of communicating research to nonspecialists. We also point out current communication gaps between science and society, particularly in the context of neurodiverse audiences and those that include neurological and psychiatric patients. Present shortcomings may turn into areas of synergy with the potential to link neuroscience education, research, and advocacy., (Copyright © 2019 the authors.)

Only a minority of individuals experiencing trauma subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from a predisposition or trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to trauma without pre-trauma conditions. Here, using the predator scent model of PTSD in rats and a longitudinal design, we measure pre-trauma brain-wide neural circuit functional connectivity, behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Freezing during predator scent exposure correlates with functional connectivity in a set of neural circuits, indicating pre-existing circuit function can predispose animals to differential fearful responses to threats. Counterintuitively, rats with lower freezing show more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a framework of pre-existing circuit function that determines threat responses, which might directly relate to PTSD-like behaviors.

Twenty years ago, I arrived in Puerto Rico from New York City to establish a neuroscience laboratory and research program on extinction of conditioned fear. The lab's first research paper appeared in the Journal of Neuroscience (Quirk et al., 2000) and has been cited >900 times. The success of this project in Puerto Rico far surpassed my original expectations. Therefore, I thought it might be useful to identify the factors responsible for this success, with the hope of facilitating the development of laboratories in diverse settings. A description of our lab practices is interspersed with personal statements from trainees hailing from Puerto Rico and other parts of Latin America. Creating an effective research and training environment depends less on the director's personality and more on the proper practice of activities that foster intellectual growth, such as journal clubs, lab meetings, and philosophy of science retreats. On a personal level, this project has been enormously gratifying. The unique environment in Puerto Rico fostered my best work, and I am very happy to have established my laboratory here., (Copyright © 2019 the authors 0270-6474/19/390776-07$15.00/0.)

Objective: Neurons in PL and IL project densely to two areas implicated in active avoidance: the basolateral amygdala (BLA) and the ventral striatum (VS). We therefore combined c-Fos immunohistochemistry with retrograde tracers to characterize signaling in platform-mediated active avoidance., Methods: Male rats  were infused with retrograde tracers (CTB, FB) into basolateral amygdala and ventral striatum and conditioned to avoid tone-signaled footshocks by stepping onto a nearby platform. In a subsequent test session, rats received either 2 unreinforced tones (avoidance retrieval) or 15 unreinforced tones (avoidance extinction) followed by analysis of c-Fos combined with fluorescent imaging of retrograde tracers., Results: Retrieval of avoidance did not activate IL neurons, but did activate PL neurons projecting to BLA, and to a lesser extent VS. Extinction of avoidance activated IL neurons projecting to both BLA and VS, as well as PL neurons projecting to VS., Conclusions: Our observation that avoidance retrieval is signaled by PL projections to BLA suggests that PL may modulate VS indirectly via BLA, and agrees with other findings implicating BLA in active avoidance. Less expected was the signaling of extinction via PL inputs to VS, which may converge with IL inputs to VS to inhibit expression of avoidance.

Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex during extinction training impairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving extinction-related plasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.

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.)

The paraventricular nucleus of the thalamus (PVT) is thought to regulate behavioral responses under emotionally arousing conditions. Reward-associated cues activate PVT neurons; however, the specific PVT efferents regulating reward seeking remain elusive. Using a cued sucrose-seeking task, we manipulated PVT activity under two emotionally distinct conditions: (1) when reward was available during the cue as expected or (2) when reward was unexpectedly omitted during the cue. Pharmacological inactivation of the anterior PVT (aPVT), but not the posterior PVT, increased sucrose seeking only when reward was omitted. Consistent with this, photoactivation of aPVT neurons abolished sucrose seeking, and the firing of aPVT neurons differentiated reward availability. Photoinhibition of aPVT projections to the nucleus accumbens or to the amygdala increased or decreased, respectively, sucrose seeking only when reward was omitted. Our findings suggest that PVT bidirectionally modulates sucrose seeking under the negative (frustrative) conditions of reward omission., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Fear is an instinctual response that's adaptive and critical for survival when it is short-lived but can lead to anxiety disorders when chronic. Studying how the brain controls our fears helps us understand the mechanisms required to recover from traumatic experiences and what goes wrong when we don't. Research in rodents has identified neural circuits and molecular mechanisms regulating fear expression. Rodent work has been amenable to translation to humans and has led to improvements in clinical therapies for anxiety disorders. The societal benefit of this type of research is magnified when performed in minority-serving institutions, offering high-caliber training opportunities to increase ethnic diversity in science.

For the past 30 years, research on the amygdala has largely focused on the genesis of defensive behaviors as its main function. This focus originated from early lesion studies and was supported by extensive anatomical, physiological, and pharmacological data. Here we argue that while much data is consistent with the fear model of amygdala function, it has never been directly tested, in part due to overreliance on the fear conditioning task. In support of the fear model, amygdala neurons appear to signal threats and/or stimuli predictive of threats. However, recent studies in a natural threat setting show that amygdala activity does not correlate with threats, but simply with the movement of the rat, independent of valence. This was true for both natural threats as well as conditioned stimuli; indeed there was no evidence of threat signaling in amygdala neurons. Similar findings are emerging for prefrontal neurons that modulate the amygdala. These recent developments lead us to propose a new conceptualization of amygdala function whereby the amygdala inhibits behavioral engagement. Moreover, we propose that the goal of understanding the amygdala will be best served by shifting away from fear conditioning toward naturalistic approach and avoidance paradigms that involve decision making and a larger repertoire of spontaneous and learned behaviors, all the while keeping an open mind., Competing Interests: Competing financial interests statement The authors declare that they have no competing financial interests.

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.)

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.)

Research in fear conditioning has provided a comprehensive picture of the neuronal circuit underlying the formation of fear memories. In contrast, our understanding of the retrieval of fear memories is much more limited. This disparity may stem from the fact that fear memories are not rigid, but reorganize over time. To bring some clarity and raise awareness about the time-dependent dynamics of retrieval circuits, we review current evidence on the neuronal circuitry participating in fear memory retrieval at both early and late time points following auditory fear conditioning. We focus on the temporal recruitment of the paraventricular nucleus of the thalamus (PVT) for the retrieval and maintenance of fear memories. Finally, we speculate as to why retrieval circuits change with time, and consider the functional strategy of recruiting structures not previously considered as part of the retrieval circuit.

Rationale: There is a high degree of comorbidity between alcohol use disorder and post-traumatic stress disorder (PTSD), but little is known about the interactions of ethanol with traumatic memories., Objectives: Using auditory fear conditioning in rats, we asked if repeated exposure to ethanol could modify the retrieval of fear memories acquired prior to ethanol exposure., Methods: Following auditory fear conditioning, Sprague-Dawley rats were given daily injections of ethanol (1.5 g/kg) or saline over 5 days. Two days later, they were given 20 trials of extinction training and then tested for extinction memory the following day. In a separate experiment, conditioned rats were given repeated ethanol injections and processed for c-Fos immunohistochemistry following a fear retrieval session., Results: Two days following the cessation of ethanol, the magnitude of conditioned fear responses (freezing and suppression of bar pressing) was significantly increased. This increase persisted the following day. Waiting 10 days following cessation of ethanol eliminated the effect on fear retrieval. In rats conditioned with low shock levels, repeated exposure to ethanol converted a sub-threshold fear memory into a supra-threshold fear memory. It also increased c-Fos expression in the prelimbic prefrontal cortex, paraventricular thalamus, and the central and basolateral nuclei of the amygdala, areas implicated in the retrieval of fear memories., Conclusions: These results suggest that repeated exposure to ethanol may exacerbate pre-existing traumatic memories.

Persistent avoidance is a prominent symptom of anxiety disorders and is often resistant to extinction-based therapies. Little is known about the circuitry mediating persistent avoidance. Using a recently described platform-mediated active avoidance task, we assessed activity in several structures with c-Fos immuno-labeling. In Task 1, rats were conditioned to avoid a tone-signaled shock by moving to a safe platform, and then were extinguished over two days. One day later, failure to retrieve extinction correlated with increased activity in the prelimbic prefrontal cortex (PL), ventral striatum (VS), and basal amygdala (BA), and decreased activity in infralimbic prefrontal cortex (IL), consistent with pharmacological inactivation studies. In Task 2, the platform was removed during extinction training and fear (suppression of bar pressing) was extinguished to criterion over 3-5 days. The platform was then returned in a post-extinction test. Under these conditions, avoidance levels were equivalent to Experiment 1 and correlated with increased activity in PL and VS, but there was no correlation with activity in IL or BA. Thus, persistent avoidance can occur independently of deficits in fear extinction and its associated structures.

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.

Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.

Drug addiction is associated with dysfunction in the medial prefrontal cortex (mPFC). However, the modifications of neuronal activity in mPFC underlying the reinforcing properties of addictive drugs are still unclear. Here we carried out single-unit recording experiments to study the neuronal activity in the prelimbic (PL) cortex of anesthetized rats, after expression of locomotor sensitization to amphetamine. In control rats, an acute injection of amphetamine induced mainly an inhibitory effect on firing rate (FR) and this response was negatively correlated with the basal FR. Sensitized rats showed a higher proportion of excited neurons and the response to amphetamine was independent of basal FR. Moreover, in control rats, acute amphetamine decreased burst rate, whereas in sensitized rats acute amphetamine increased burst rate. These findings indicate that amphetamine sensitization renders mPFC neurons hyperexcitable. Taken together, these data support the hypothesis that early withdrawal is associated with an increase in the activity of the mPFC, which could strengthen the PL-Nucleus Accumbens connection, thus facilitating amphetamine-induced locomotor sensitization., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Previous rodent studies have implicated the infralimbic (IL) subregion of the medial prefrontal cortex in extinction of auditory fear conditioning. However, these studies used pharmacological inactivation or electrical stimulation techniques, which lack temporal precision and neuronal specificity. Here, we used an optogenetic approach to either activate (with channelrhodopsin) or silence (with halorhodopsin) glutamatergic IL neurons during conditioned tones delivered in one of two phases: extinction training or extinction retrieval. Activating IL neurons during extinction training reduced fear expression and strengthened extinction memory the following day. Silencing IL neurons during extinction training had no effect on within-session extinction, but impaired the retrieval of extinction the following day, indicating that IL activity during extinction tones is necessary for the formation of extinction memory. Surprisingly, however, silencing IL neurons optogenetically or pharmacologically during the retrieval of extinction 1 day or 1 week following extinction training had no effect. Our findings suggest that IL activity during extinction training likely facilitates storage of extinction in target structures, but contrary to current models, IL activity does not appear to be necessary for retrieval of extinction memory., (Copyright © 2015 the authors 0270-6474/15/353607-09$15.00/0.)

The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders.

Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.

Individuals use both passive and active defensive responses to environmental threats. Much is known about the neural circuits of passive defensive responses (e.g., freezing), but less is known about the substrates of active defensive responses (e.g., avoidance). We developed an active avoidance task in which rats learn to avoid a tone-signaled footshock by stepping onto a nearby platform. An advantage of this task is that freezing, which can interfere with avoidance, is reduced, thereby facilitating comparison of the effects of manipulations on avoidance versus freezing. After 10 d of avoidance training, rats were infused with muscimol to pharmacologically inactivate the prelimbic cortex (PL), infralimbic cortex (IL), ventral striatum (VS), or basolateral amygdala (BLA). Inactivating PL, VS, or BLA all impaired avoidance expression, but these areas differed with respect to freezing. Inactivating BLA decreased freezing consistent with loss of the tone-shock association, whereas inactivation of VS increased freezing consistent with loss of avoidance memory. Inactivation of PL had no effect on freezing. Inactivation of IL did not impair avoidance expression but did impair avoidance extinction. Our findings suggest that active avoidance is mediated by prefrontal-striatal circuits, which may be overactive in individuals suffering from trauma-related disorders., (Copyright © 2014 the authors 0270-6474/14/349736-07$15.00/0.)

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.

The acquisition and expression of conditioned fear depends on prefrontal-amygdala circuits. Auditory fear conditioning increases the tone responses of lateral amygdala neurons, but the increase is transient, lasting only a few hundred milliseconds after tone onset. It was recently reported that that the prelimbic (PL) prefrontal cortex transforms transient lateral amygdala input into a sustained PL output, which could drive fear responses via projections to the lateral division of basal amygdala (BL). To explore the possible mechanisms involved in this transformation, we developed a large-scale biophysical model of the BL-PL network, consisting of 850 conductance-based Hodgkin-Huxley-type cells, calcium-based learning, and neuromodulator effects. The model predicts that sustained firing in PL can be derived from BL-induced release of dopamine and norepinephrine that is maintained by PL-BL interconnections. These predictions were confirmed with physiological recordings from PL neurons during fear conditioning with the selective β-blocker propranolol and by inactivation of BL with muscimol. Our model suggests that PL has a higher bandwidth than BL, due to PL's decreased internal inhibition and lower spiking thresholds. It also suggests that variations in specific microcircuits in the PL-BL interconnection can have a significant impact on the expression of fear, possibly explaining individual variability in fear responses. The human homolog of PL could thus be an effective target for anxiety disorders.

Background: The most effective treatment for posttraumatic stress disorder (PTSD) is exposure therapy, which aims to facilitate extinction of conditioned fear. Recent evidence suggests that brain-derived neurotrophic factor (BDNF) facilitates extinction learning. This study assessed whether the Met-66 allele of BDNF, which results in lower activity-dependent secretion, predicts poor response to exposure therapy in PTSD., Methods: Fifty-five patients with PTSD underwent an 8-week exposure-based cognitive behavior therapy program and provided mouth swabs or saliva to extract genomic DNA to determine their BDNF Val66Met genotype (30 patients with the Val/Val BDNF allele, 25 patients with the Met-66 allele). We examined whether BDNF genotype predicted reduction in PTSD severity following exposure therapy., Results: Analyses revealed poorer response to exposure therapy in the PTSD patients with the Met-66 allele of BDNF compared with patients with the Val/Val allele. Pretreatment Clinician Administered PTSD Scale severity and BDNF Val66Met polymorphism predicted response to exposure therapy using hierarchical regression., Conclusions: This study provides the first evidence that the BDNF Val66Met genotype predicts response to cognitive behavior therapy in PTSD and is in accord with evidence that BDNF facilitates extinction learning., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

It is thought that discrete subregions of the medial prefrontal cortex (mPFC) regulate different aspects of appetitive behavior, however, physiological support for this hypothesis has been lacking. In the present study, we used multichannel single-unit recording to compare the response of neurons in the prelimbic (PL) and infralimbic (IL) subregions of the mPFC, in rats pressing a lever to obtain sucrose pellets on a variable interval schedule of reinforcement (VI-60). Approximately 25% of neurons in both structures exhibited prominent excitatory responses during rewarded, but not unrewarded, lever presses. The time courses of reward responses in PL and IL, however, were markedly different. Most PL neurons exhibited fast and transient responses at the delivery of sucrose pellets, whereas most IL neurons exhibited delayed and prolonged responses associated with the collection of earned sucrose pellets. We further examined the functional significance of reward responses in IL and PL with local pharmacological inactivation. IL inactivation significantly delayed the collection of earned sucrose pellets, whereas PL inactivation produced no discernible effects. These findings support the hypothesis that PL and IL signal distinct aspects of appetitive behavior, and suggest that IL signaling facilitates reward collection.

The prefrontal cortex (PFC) regulates emotional responses, but it is unclear how PFC integrates diverse inputs to select the appropriate response. We therefore evaluated the contribution of basolateral amygdala (BLA) and ventral hippocampus (vHPC) inputs to fear signaling in the prelimbic (PL) cortex, a PFC region critical for the expression of conditioned fear. In conditioned rats trained to press for food, BLA inactivation decreased the activity of projection cells in PL, and reduced PL conditioned tone responses. In contrast, vHPC inactivation decreased activity of interneurons in PL and increased PL conditioned tone responses. Consistent with hippocampal gating of fear after extinction, vHPC inactivation increased fear and PL pyramidal activity in extinguished, but not in conditioned, rats. These results suggest a prefrontal circuit whereby hippocampus gates amygdala-based fear. Thus, deficient hippocampal inhibition of PFC may underlie emotional disorders, especially in light of reduced hippocampal volume observed in depression and PTSD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Anxiety disorders are characterized by specific emotions, thoughts and physiological responses. Little is known, however, about the relationship between psychological/personality indices of anxiety responses to fear stimuli., Methods: We studied this relationship in healthy subjects by comparing scores on psychological and personality questionnaires with results of an experimental fear conditioning paradigm using a visual conditioned stimulus (CS). We measured skin conductance response (SCR) during habituation, conditioning, and extinction; subsequently testing for recall and renewal of fear 24 hours later., Results: We found that multiple regression models explained 45% of the variance during conditioning to the CS+, and 24% of the variance during renewal of fear to the CS+. Factors that explained conditioning included lower levels of conscientiousness, increased baseline reactivity (SCL), and response to the shock (UCR). Low levels of extraversion correlated with greater renewal. No model could be found to explain extinction learning or extinction recall to the CS+., Conclusions: The lack of correlation of fear extinction with personality and neuropsychological indices suggests that extinction may be less determined by trait variables and cognitive state, and may depend more on the subject's current emotional state. The negative correlation between fear renewal and extraversion suggests that this personality characteristic may protect against post-treatment relapse of symptoms of anxiety disorders.

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.

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.