Promoting crucial team building, collaboration, and communication skills in graduate students through interactive retreats.

Biomedical graduate students receive intensive training in their scientific area of interest yet need additional skills for successful scientific careers. Our aim was to promote team building, improve collaborations and enhance communication skills. An off-site yearly retreat was organized for the graduate students in our NIH-funded Research Initiative for Scientific Enhancement (RISE) graduate training program. Retreat themes were addressed through short presentations, case studies, live podcasts, webinars, focus groups, role-play, and breakout sessions with various team building exercises to practice communication skills and identify abilities, knowledge, values, and behaviors. Trainees gave short presentations and served as discussion leaders on topics related to the central theme. Expert guest speakers participated in discussion sessions with the trainees. Trainees evaluated the retreats at the end. A total of 48 trainees, 12 RISE Program faculty and staff, and 26 external speakers from industry, academia, media/journalism, the arts, psychology, and holistic medical fields participated over 9 years. The overall average benefit of the in-person retreats was rated 4.80 on a Likert scale of 1-5 by trainees. Trainees particularly enjoyed the informal interactions with program faculty, staff, and fellow trainees. They appreciated the opportunity to learn soft skills, such as interpersonal communication, conflict resolution, and leadership. Two additional retreats conducted virtually because of the COVID-19 pandemic were perceived as less beneficial. We conclude that off-site interactive retreats are a valuable tool for enhancing soft skills and a sense of team identity in a biomedical sciences graduate program, while covering important issues related to scientific careers.NEW & NOTEWORTHY Off-site interactive science-related retreats are a valuable tool for enhancing soft skills and sense of team identity in a biomedical sciences graduate program, while covering important issues related to pursuing a career in science. There are many perceived benefits, so we encourage other training programs to include a similar type of regular activity in students' training with the goal of improving trainee well-being and supporting their academic and research productivity.

Sex-dependent effects of angiotensin II type 1 receptor blocker on molecular and behavioral changes induced by single prolonged stress.

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that not only entails alterations in fear behavior and anxiety but also includes neuroendocrine dysfunctions involving the hypothalamic pituitary adrenal (HPA) axis and the renin-angiotensin system. Recent preclinical studies demonstrate that activation of the angiotensin type 1 receptor (AT1R) in the paraventricular region of the hypothalamus (PVR) promotes anxiety-like behaviors and enables microglia proliferation. An increase in microglia and anxiety-like behavior also occurs in the PTSD animal model single-prolonged stress (SPS). In the present study, we tested whether AT1Rs contribute to the effects of SPS on behavior and microglia in brain structures important for HPA axis regulation and fear behavior. To test this, male and female animals were exposed to SPS and then given the oral AT1R antagonist candesartan beginning one week later. Candesartan did not alter auditory fear conditioning or extinction in SPS-exposed male or female animals. However, we found that the male animals exposed to SPS showed increased anxiety-like behavior, which was reversed by candesartan. In contrast, neither SPS nor candesartan altered anxiety-like behavior in the female animals. At the molecular level, SPS increased the cellular expression of AT1Rs in the PVR of male animals and candesartan reversed this effect, whereas AT1Rs in the PVR of females were unaltered by either SPS or candesartan. Iba1-expressing microglia increased in the PVR after SPS exposure and was reversed by candesartan in both sexes suggesting that SPS stimulates AT1Rs to increase microglia in the PVR. Collectively, these results suggest that the contribution of AT1Rs to the molecular and behavioral effects of SPS is sex-dependent.

Purinergic P2X7 receptor-mediated inflammation precedes PTSD-related behaviors in rats.

Clinical evidence has linked increased peripheral pro-inflammatory cytokines with post-traumatic stress disorder (PTSD) symptoms. However, whether inflammation contributes to or is a consequence of PTSD is still unclear. Previous research shows that stress can activate purinergic P2X7 receptors (P2X7Rs) on microglia to induce inflammation and behavioral changes. In this investigation, we examined whether P2X7Rs contribute to the development of PTSD-like behaviors induced by single prolonged stress (SPS) exposure in rats. Consistent with the literature, exposing adult male and female rats to SPS produced a PTSD-like phenotype of impaired fear extinction and extinction of cue-induced center avoidance one week after exposure. Next, we examined if inflammation precedes the behavioral manifestations. Three days after SPS exposure, increased inflammatory cytokines were found in the blood and hippocampal microglia showed increased expression of the P2X7R, IL-1ß, and TNF-α, suggesting increased peripheral and central inflammation before the onset of impaired fear extinction. In addition, SPS-exposed animals with impaired fear extinction recall also had more Iba1-positive microglia expressing the P2X7R in the ventral hippocampus. To determine whether P2X7Rs contribute to the PTSD-related behaviors induced by SPS exposure, we gave ICV infusions of the P2X7R antagonist, A-438079, for one week starting the day of SPS exposure. Blocking P2X7Rs prevented the SPS-induced impaired fear extinction and extinction of cue-induced center avoidance in male and female rats, suggesting that SPS activates P2X7Rs which increase inflammation to produce a PTSD-like phenotype.

Infusion of C20:0 ceramide into ventral hippocampus triggers anhedonia-like behavior in female and male rats.

Increased long-chain C20:0 ceramides have been found in the serum of patients with depression. Moreover, ceramides are linked with increased microglia reactivity and inflammatory cytokine production, which are associated with depression. Since ceramides can readily cross the blood brain barrier, peripheral C20:0 ceramides could enter the brain, activate microglia, and induce depressive-like behavior. In this study, we determined whether localized infusion of C20:0 ceramides into the ventral hippocampus (VH) of rats is sufficient to activate microglia and induce depressive-like behaviors. Adult male and female rats received infusions of C20:0 ceramides or vehicle solution every other day for 2 weeks. After the third infusion, C20:0-infused animals showed reduced sucrose preference suggesting anhedonia-like behavior. In contrast, infusions of C20:0 ceramides did not affect immobility in the forced swim test or sucrose grooming suggesting that the behavioral effects of ceramides are task dependent. Furthermore, C20:0-infusions did not increase Iba-1 + microglia or inflammatory markers in the VH suggesting that localized increases in C20:0 ceramides in the VH are sufficient to induce anhedonia-like behavior without microglia activation.

High-Fat Diet and Short-Term Unpredictable Stress Increase Long-Chain Ceramides Without Enhancing Behavioral Despair.

Clinical and preclinical studies suggest that increases in long-chain ceramides in blood may contribute to the development of depressive-like behavior. However, which factors contribute to these increases and whether the increases are sufficient to induce depressive-like behaviors is unclear. To begin to address this issue, we examined the effects of high fat diet (HFD) and short-term unpredictable (STU) stress on long-chain ceramides in the serum of male and female rats. We found that brief exposure to HFD or unpredictable stress was sufficient to induce selective increases in the serum concentrations of long-chain ceramides, associated with depression in people. Furthermore, combined exposure to HFD and unpredictable stress caused a synergistic increase in C16:0, C16:1, and C18:0 ceramides in both sexes and C18:1 and C24:1 in males. However, the increased peripheral long-chain ceramides were not associated with increases in depressive-like behaviors suggesting that increases in serum long-chain ceramides may not be associated with the development of depressive-like behaviors in rodents.

Sex-dependent effects of microglial reduction on impaired fear extinction induced by single prolonged stress.

Single prolonged stress (SPS) is a preclinical rodent model for studying post-traumatic stress disorder (PTSD)-like behaviors. Previously we found that increased expression of the microglial marker Iba-1 in the ventral hippocampus after SPS exposure was associated with impaired fear extinction, suggesting that microglial activity contributed to the SPS-induced behavioral changes. To test this, we examined whether reducing microglia with the colony-stimulating factor 1 receptor blocker, PLX3397, in the diet would prevent the SPS-induced extinction impairment. Male rats exposed to SPS showed enhanced fear acquisition and impaired fear extinction memory. Adding PLX3397 to the diet prevented these behavioral changes. In contrast, PLX3397 did not prevent SPS from impairing fear extinction memory in the female rats. Despite the sex-dependent behavioral effects, we found a reduced number and area fraction of Iba-1+ microglia in both male and female rats suggesting that PLX3397 had similar effects on microglia in both sexes. Altogether, these results suggest that microglia contribute to the behavioral changes induced by SPS in male but not female rats.

Plasticity of GluN1 at Ventral Hippocampal Synapses in the Infralimbic Cortex.

Although the infralimbic cortex (IL) is not thought to play a role in fear acquisition, recent experiments found evidence that synaptic plasticity is occurring at ventral hippocampal (vHPC) synapses in IL during auditory fear acquisition as measured by changes in the N-methyl-D-aspartate (NMDA) receptor-mediated currents in male rats. These electrophysiological data suggest that fear conditioning changes the expression of NMDA receptors on vHPC-to-IL synapses. To further evaluate the plasticity of NMDA receptors at this specific synapse, we injected AAV particles expressing channelrhodopsin-EYFP into the vHPC of male and female rats to label vHPC projections with EYFP. To test for NMDA receptor changes in vHPC-to-IL synapses after fear learning, we used fluorescence-activated cell sorting (FACS) to quantify synaptosomes isolated from IL tissue punches that were positive for EYFP and the obligatory GluN1 subunit. More EYFP+/GluN1+ synaptosomes with greater average expression of GluN1 were isolated from male rats exposed to auditory fear conditioning (AFC) than those exposed to context and tones only or to contextual fear conditioning (CFC), suggesting that AFC increased NMDA receptor expression in males. In a second experiment, we found that pairing the tones and shocks was required to induce the molecular changes and that fear extinction did not reverse the changes. In contrast, females showed similar levels of EYFP+/GluN1+ synaptosomes in all behavioral groups. These findings suggest that AFC induces synaptic plasticity of NMDA receptors in the vHPC-to-IL projection in males, while female rats rely on different synaptic mechanisms.

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities.

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.

Learning-induced intrinsic and synaptic plasticity in the rodent medial prefrontal cortex.

In rodents, the anterior cingulate (ACC), prelimbic (PL), and infralimbic cortex (IL) comprise the medial prefrontal cortex (mPFC). Through extensive connections with cortical and subcortical structures, the mPFC plays a key modulatory role in the neuronal circuits underlying associative fear and reward learning. In this article, we have compiled the evidence that associative learning induces plasticity in both the intrinsic and synaptic excitability of mPFC neurons to modulate conditioned fear and cocaine seeking behavior. The literature highlights the accumulating evidence that plasticity in the intrinsic excitability of mPFC neurons represents a major cellular mechanism that interacts with synaptic changes to alter the impact of the mPFC on fear and reward circuits.

TGFßRI antagonist inhibits HIV-1 Nef-induced CC chemokine family ligand 2 (CCL2) in the brain and prevents spatial learning impairment.

BACKGROUND: HIV-1-associated neurocognitive disorders (HAND) progression is related to continued inflammation despite undetectable viral loads and may be caused by early viral proteins expressed by latently infected cells. Astrocytes represent an HIV reservoir in the brain where the early viral neurotoxin negative factor (Nef) is produced. We previously demonstrated that astrocytic expression of Nef in the hippocampus of rats causes inflammation, macrophage infiltration, and memory impairment. Since these processes are affected by TGFß signaling pathways, and TGFß-1 is found at higher levels in the central nervous system of HIV-1+ individuals and is released by astrocytes, we hypothesized a role for TGFß-1 in our model of Nef neurotoxicity. METHODS: To test this hypothesis, we compared cytokine gene expression by cultured astrocytes expressing Nef or green fluorescent protein. To determine the role of Nef and a TGFßRI inhibitor on memory and learning, we infused astrocytes expressing Nef into the hippocampus of rats and then treated them daily with an oral dose of SD208 (10 mg/kg) or placebo for 7 days. During this time, locomotor activity was recorded in an open field and spatial learning tested in the novel location recognition paradigm. Postmortem tissue analyses of inflammatory and signaling molecules were conducted using immunohistochemistry and immunofluorescence. RESULTS: TGFß-1 was induced in cultures expressing Nef at 24 h followed by CCL2 induction which was prevented by blocking TGFßRI with SD208 (competitive inhibitor). Interestingly, Nef seems to change the TGFßRI localization as suggested by the distribution of the immunoreactivity. Nef caused a deficit in spatial learning that was recovered upon co-administration of SD208. Brain tissue from Nef-treated rats given SD208 showed reduced CCL2, phospho-SMAD2, cluster of differentiation 163 (CD163), and GFAP immunoreactivity compared to the placebo group. CONCLUSIONS: Consistent with our previous findings, rats treated with Nef showed deficits in spatial learning and memory in the novel location recognition task. In contrast, rats treated with Nef + SD208 showed better spatial learning suggesting that Nef disrupts memory formation in a TGFß-1-dependent manner. The TGFßRI inhibitor further reduced the induction of inflammation by Nef which was concomitant with decreased TGFß signaling. Our findings suggest that TGFß-1 signaling is an intriguing target to reduce neuroHIV.

Plasticity of NMDA Receptors at Ventral Hippocampal Synapses in the Infralimbic Cortex Regulates Cued Fear.

The medial prefrontal cortex (mPFC) processes contextual information from the hippocampus to generate appropriate fear responses. In rodents, one path for sending contextual information to the mPFC is via the direct projections from the ventral hippocampus (vHC) to the infralimbic cortex (IL). Plasticity in the synaptic communication from the vHC to the IL could contribute to the behavioral changes produced by the acquisition and extinction of conditioned fear. To examine this possibility, we used optogenetic stimulation of vHC synapses in brain slices from trained rats. We found that fear acquisition reduced NMDA receptor (NMDAR) currents at vHC synapses onto IL pyramidal neurons. The depression of NMDAR currents reversed more efficiently after extinction in the conditioning context than extinction in a novel context. Moreover, a cohort of animals that exhibited poor extinction retrieval failed to reverse the plasticity induced by fear conditioning. In addition, ex vivo application of brain-derived neurotrophic factor (BDNF), which is known to simulate extinction in IL, reversed this conditioning-induced plasticity mimicking extinction. Therefore, we have identified a novel mechanism that modulates conditioned fear via changes in NMDAR current at vHC synapses onto IL pyramidal neurons. Disruption of this mechanism could contribute to the abnormal contextual modulation of fear seen in posttraumatic stress disorder (PTSD).

Hsp90 and FKBP51: complex regulators of psychiatric diseases.

Mood disorders affect nearly a quarter of the world's population. Therefore, understanding the molecular mechanisms underlying these conditions is of great importance. FK-506 binding protein 5 (FKBP5) encodes the FKBP51 protein, a heat shock protein 90 kDa (Hsp90) co-chaperone, and is a risk factor for several affective disorders. FKBP51, in coordination with Hsp90, regulates glucocorticoid receptor (GR) activity via a short negative feedback loop. This signalling pathway rapidly restores homeostasis in the hypothalamic-pituitary-adrenal (HPA) axis following stress. Expression of FKBP5 increases with age through reduced DNA methylation. High levels of FKBP51 are linked to GR resistance and reduced stress coping behaviour. Moreover, common allelic variants in the FKBP5 gene are associated with increased risk of developing affective disorders like anxiety, depression and post-traumatic stress disorder (PTSD). This review highlights the current understanding of the Hsp90 co-chaperone, FKBP5, in disease from both human and animal studies. In addition, FKBP5 genetic implications in the clinic involving life stress exposure, gender differences and treatment outcomes are discussed.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Dynamic expression of FKBP5 in the medial prefrontal cortex regulates resiliency to conditioned fear.

The factors influencing resiliency to the development of post-traumatic stress disorder (PTSD) remain to be elucidated. Clinical studies associate PTSD with polymorphisms of the FK506 binding protein 5 (FKBP5). However, it is unclear whether changes in FKBP5 expression alone could produce resiliency or susceptibility to PTSD-like symptoms. In this study, we used rats as an animal model to examine whether FKBP5 in the infralimbic (IL) or prelimbic (PL) medial prefrontal cortex regulates fear conditioning or extinction. First, we examined FKBP5 expression in IL and PL during fear conditioning or extinction. In contrast to the stable expression of FKBP5 seen in PL, FKBP5 expression in IL increased after fear conditioning and remained elevated even after extinction suggesting that IL FKBP5 levels may modulate fear conditioning or extinction. Consistent with this possibility, reducing basal FKBP5 expression via local infusion of FKBP5-shRNA into IL reduced fear conditioning. Furthermore, reducing IL FKBP5, after consolidation of the fear memory, enhanced extinction memory indicating that IL FKBP5 opposed formation of the extinction memory. Our findings demonstrate that lowering FKBP5 expression in IL is sufficient to both reduce fear acquisition and enhance extinction, and suggest that lower expression of FKBP5 in the ventral medial prefrontal cortex could contribute to resiliency to PTSD.

Contextual fear conditioning depresses infralimbic excitability.

Patients with posttraumatic stress disorder (PTSD) show hypo-active ventromedial prefrontal cortices (vmPFC) that correlate with their impaired ability to discriminate between safe and dangerous contexts and cues. Previously, we found that auditory fear conditioning depresses the excitability of neurons populating the homologous structure in rodents, the infralimbic cortex (IL). However, it is undetermined if IL depression was mediated by the cued or contextual information. The objective of this study was to examine whether contextual information was sufficient to depress IL neuronal excitability. After exposing rats to context-alone, pseudoconditioning, or contextual fear conditioning, we used whole-cell current-clamp recordings to examine the excitability of IL neurons in prefrontal brain slices. We found that contextual fear conditioning reduced IL neuronal firing in response to depolarizing current steps. In addition, neurons from contextual fear conditioned animals showed increased slow afterhyperpolarization potentials (sAHPs). Moreover, the observed changes in IL excitability correlated with contextual fear expression, suggesting that IL depression may contribute to the encoding of contextual fear.

Candesartan ameliorates impaired fear extinction induced by innate immune activation.

Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 µg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 µg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 µg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 µg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 µg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD.

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase.

Beyond the GRE: using a composite score to predict the success of Puerto Rican students in a biomedical PhD program.

The use and validity of the Graduate Record Examination General Test (GRE) to predict the success of graduate school applicants is heavily debated, especially for its possible impact on the selection of underrepresented minorities into science, technology, engineering, and math fields. To better identify candidates who would succeed in our program with less reliance on the GRE and grade point average (GPA), we developed and tested a composite score (CS) that incorporates additional measurable predictors of success to evaluate incoming applicants. Uniform numerical values were assigned to GPA, GRE, research experience, advanced course work or degrees, presentations, and publications. We compared the CS of our students with their achievement of program goals and graduate school outcomes. The average CS was significantly higher in those students completing the graduate program versus dropouts (p < 0.002) and correlated with success in competing for fellowships and a shorter time to thesis defense. In contrast, these outcomes were not predicted by GPA, science GPA, or GRE. Recent implementation of an impromptu writing assessment during the interview suggests the CS can be improved further. We conclude that the CS provides a broader quantitative measure that better predicts success of students in our program and allows improved evaluation and selection of the most promising candidates.

Spontaneous recovery of fear reverses extinction-induced excitability of infralimbic neurons.

In rodents, the infralimbic (IL) region of the medial prefrontal cortex plays a key role in the recall of fear extinction. Previously we showed that fear conditioning decreases the intrinsic excitability of IL neurons, and that fear extinction reverses the depressed excitability. In the current study, we examined the time course of the extinction-induced changes in adolescent rats. Immediately after extinction, IL neurons continued to show depressed excitability. However 4 hours after extinction, IL neurons showed an increase in evoked spikes that correlated with a reduced fast afterhyperpolarizing potential. This suggests that acquisition of fear extinction induces an increase in spike firing 4 hours later, during the consolidation of extinction. We also examined IL excitability in a group of rats that showed spontaneous recovery of fear 17 days after extinction (SR group). Similar to neurons after fear conditioning, IL neurons from the SR group showed depressed intrinsic excitability compared to neurons 4 hours after extinction, suggesting that extinction-induced enhancement in intrinsic excitability decreases with time reverting back to a depressed state. These results suggest that plasticity in IL contributes to the spontaneous recovery of fear and preventing this depression of IL excitability could prolong fear extinction.

Glutamate metabolism and HIV-associated neurocognitive disorders.

HIV-1 infection can lead to neurocognitive impairment collectively known as HIV-associated neurocognitive disorders (HAND). Although combined antiretroviral treatment (cART) has significantly ameliorated HIV's morbidity and mortality, persistent neuroinflammation and neurocognitive dysfunction continue. This review focuses on the current clinical and molecular evidence of the viral and host factors that influence glutamate-mediated neurotoxicity and neuropathogenesis as an important underlying mechanism during the course of HAND development. In addition, discusses potential pharmacological strategies targeting the glutamatergic system that may help prevent and improve neurological outcomes in HIV-1-infected subjects.

Modulating fear extinction memory by manipulating SK potassium channels in the infralimbic cortex.

Fear extinction correlates with increased infralimbic (IL) neuronal excitability. Since small conductance Ca(2+)-dependent K(+) (SK) channels modulate neuronal excitability and certain types of learning and memory, pharmacological modulation of SK channels could be used to regulate IL excitability and fear extinction. To test this, we first determined the effect of blocking SK channels with apamin on the intrinsic excitability of IL pyramidal neurons in brain slices. In whole-cell patch-clamp recordings, apamin increased the number of spikes evoked by a depolarizing current pulse, increased the firing frequency, and reduced the fast afterhyperpolarizing potential (fAHP) indicating that blockade of SK channels could be used to enhance the intrinsic excitability of IL neurons. Next, we assessed whether SK channels in IL regulate extinction of conditioned fear by infusing apamin into IL of fear conditioned rats prior to extinction training. Apamin infusion did not affect conditioned freezing at the beginning of the extinction session or within-session extinction. However, the following day, apamin-infused rats showed significantly less conditioned freezing. To further examine the importance of SK channels in IL in fear extinction, we assessed the effect of the SK channel activator DCEBIO on IL neuronal excitability and fear extinction. Activation of SK channels with DCEBIO decreased the number of evoked spikes, reduced the firing frequency, and enhanced the fAHP of IL neurons. Infusion of DCEBIO into IL prior to fear extinction impaired recall of fear extinction without affecting acquisition of extinction. Taken together, these findings suggest that SK channels are involved in regulating IL excitability and extinction-induced plasticity. Therefore, SK channels are a potential target for the development of new pharmacological treatments to facilitate extinction in patients suffering from anxiety disorders.