Stephen Maren

Stephen Maren
Texas A&M University | TAMU · Department of Psychology

Doctor of Philosophy
Deciphering brain circuits mediating emotional learning and memory

About

197
Publications
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Introduction
Memories for emotional, particularly fearful, events are vivid, visceral, and enduring. But dysfunction in this system can result in anxiety, panic and post-traumatic stress disorder, for example. Research in my laboratory seeks to understand the brain circuits and cellular mechanisms underlying the encoding, storage, retrieval, and extinction of aversive memories, and how dysfunction in these circuits and processes contributes to anxiety disorders.

Publications

Publications (197)
Article
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The basolateral amygdala (BLA) complex receives dense cholinergic projections from the nucleus basalis of Meynert (NBM) and the horizontal limb of the diagonal band of Broca (HDB). The present experiments examined whether these projections regulate the formation, extinction, and renewal of fear memories. This was achieved by employing a Pavlovian f...
Article
Recent data reveal that the thalamic nucleus reuniens (RE) has a critical role in the extinction of conditioned fear. Muscimol (MUS) infusions into the RE impair within-session extinction of conditioned freezing and result in poor long-term extinction memories in rats. Although this suggests that RE inactivation impairs extinction learning, it is a...
Article
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Fear and anxiety-based disorders are highly debilitating and among the most prevalent psychiatric disorders. These disorders are associated with abnormal network oscillations in the brain, yet a comprehensive understanding of the role of network oscillations in the regulation of aversively motivated behavior is lacking. In this review, we examine t...
Article
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Extinction learning is central to exposure-based behavioral therapies for reducing fear and anxiety in humans. However, patients with fear and anxiety disorders are often resistant to extinction. Moreover, trauma and stress-related disorders are highly prone to relapse and are twice as likely to occur in females compared to males, suggesting that f...
Article
The increased susceptibility of women to stress and trauma-related disorders compared to men suggests a role for ovarian hormones in modulating fear and anxiety. In both humans and rodents, estrogen and progesterone have been shown to influence fear learning during acquisition, expression, and extinction. Recently, we showed that allopregnanolone (...
Preprint
Full-text available
Extinction learning is central to exposure-based behavioral therapies for reducing fear and anxiety in humans. However, patients with fear and anxiety disorders are often resistant to extinction. Moreover, trauma and stress-related disorders are highly prone to relapse and are twice as likely to occur in females compared to males, suggesting that f...
Article
Full-text available
Background In both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that become independent of the BLA with the passage of time. Methods We systematically examined the role for the BLA in th...
Preprint
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Background In both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that they become independent of the BLA with the passage of time. Methods We systematically examined the role for the BLA...
Preprint
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Advances in behavioral optogenetics are limited by the absence of high-throughput pipelines for the automated analysis of behavior in freely behaving animals. Although a variety of AI algorithms has been proposed that enable automation of behavioral analysis, existing methods are generally low-throughput. In addition, optogenetic manipulation of ne...
Article
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Reconsolidation may be a viable therapeutic target to inhibit pathological fear memories. In the clinic, incidental or imaginal reminders are used for safe retrieval of traumatic memories of experiences that occurred elsewhere. However, it is unknown whether indirectly retrieved traumatic memories are sensitive to disruption. Here we used a backwar...
Article
Considerable work indicates that instrumental responding is context-dependent, but the neural mechanisms underlying this phenomenon are poorly understood. Given the important role for the hippocampal formation in contextual processing, we hypothesized that reversible inactivation of the hippocampus would impair the context-dependence of active avoi...
Article
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Environmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show th...
Preprint
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Considerable work indicates that instrumental responding is context-dependent, but the neural mechanisms underlying this phenomenon are poorly understood. Given the important role for the hippocampal formation in contextual processing, we hypothesized that reversible inactivation of the hippocampus would impair the context-dependence of active avoi...
Preprint
Full-text available
Environmental contexts and associative learning can inform animals of potential threats, though it is currently unknown how contexts bias defensive transitions. Here we investigated context-dependent flight responses in the Pavlovian serial-compound stimulus (SCS) paradigm. We show here that SCS-evoked flight behavior in male and female rats is dep...
Article
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This article reviews the behavioral neuroscience of extinction, the phenomenon in which a behavior that has been acquired through Pavlovian or instrumental (operant) learning decreases in strength when the outcome that reinforced it is removed. Behavioral research indicates that neither Pavlovian nor operant extinction depends substantially on eras...
Article
Considerable work demonstrates that Pavlovian fear conditioning depends on N-methyl-D-aspartate (NMDA) receptor-dependent plasticity within the amygdala. In addition, the bed nucleus of the stria terminalis (BNST) has also been implicated in fear conditioning, particularly in the expression of fear to poor predictors of threat. We recently found th...
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Stress impairs extinction learning and these deficits depend, in part, on stress-induced norepinephrine release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered s...
Article
Recent work indicates that the bed nucleus of the stria terminalis (BNST) is critically involved in the regulation of conditioned fear responses to unpredictable threats. Here we examined whether the involvement of the BNST in contextual fear conditioning in male rats depends on the imminence of shock after placement in the conditioning chamber. Sp...
Article
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Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear condit...
Preprint
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Previous work indicates that the bed nucleus of the stria terminalis (BNST) is involved in defensive freezing to unpredictable Pavlovian conditioned stimuli (Goode et al., 2019). Here we show that the BNST mediates freezing to contexts paired with remote (unpredictable), but not imminent (predictable), footshock. Rats underwent a fear conditioning...
Article
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Recent work reveals that the extinction of conditioned fear depends upon the interval between conditioning and extinction. Extinction training that takes place within minutes to hours after fear conditioning fails to produce a long-term extinction memory, a phenomenon known as the immediate extinction deficit (IED). Neurobiological evidence suggest...
Article
Learning and remembering the context in which events occur requires interactions between the hippocampus (HPC) and medial prefrontal cortex (mPFC). The nucleus reuniens (RE) is a ventral midline thalamic nucleus that coordinates activity in the mPFC and HPC and is involved in spatial and contextual memory. We recently found that the RE is critical...
Article
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The medial prefrontal cortex (mPFC) plays an essential role in regulating emotion, including inhibiting fear when danger has passed. The extinction of fear, however, is labile and a number of factors, including stress, cause extinguished fear to relapse. Here we show that fear relapse in rats limits single-unit activity among infralimbic (IL) neuro...
Article
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Post-traumatic stress disorder (PTSD) afflicts approximately 8% of the United States population and represents a significant public health burden, but the underlying neural mechanisms of this and other anxiety- and stressor-related disorders are largely unknown. Within the last few decades, several preclinical models of PSTD have been developed to...
Article
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The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversib...
Article
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Background Comorbidity of anxiety disorders, stressor- and trauma-related disorders, and substance use disorders is extremely common. Moreover, therapies that reduce pathological fear and anxiety on the one hand, and drug-seeking on the other, often prove short-lived and are susceptible to relapse. Considerable advances have been made in the study...
Article
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The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological...
Article
Full-text available
The nucleus reuniens (RE) is a ventral midline thalamic nucleus that interconnects the medial prefrontal cortex (mPFC) and hippocampus (HPC). Considerable data indicate that HPC-mPFC circuits are involved in contextual and spatial memory; however, it is not clear whether the RE mediates the acquisition or retrieval of these memories. To examine thi...
Article
Over the years Pavlovian fear conditioning has proved to be a powerful model to investigate the neural underpinnings of aversive associative memory formation. Although it is well appreciated that plasticity occurring at excitatory synapses within the basolateral complex of the amygdala (BLA) plays a critical role in associative memory formation, re...
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In the version of this article initially published, the traces in Fig. 1j and in Fig. 1k, right, were duplicated from the corresponding traces in Fig. 1c, bottom, and Fig. 1d, bottom right. The error has been corrected in the HTML and PDF versions of the article.
Preprint
Full-text available
The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversib...
Preprint
Full-text available
The nucleus reuniens (RE) is a ventral midline thalamic nucleus that interconnects the medial prefrontal cortex (mPFC) and hippocampus (HPC). Considerable data indicate that HPC-mPFC circuits are involved in contextual and spatial memory; however, it is not clear whether the RE mediates the acquisition or retrieval of these memories. To examine thi...
Article
Full-text available
The locus coeruleus norepinephrine (LC-NE) system plays a broad role in learning and memory. Here we begin with an overview of the LC-NE system. We then consider how both direct and indirect manipulations of the LC-NE system affect cued and contextual aversive learning and memory. We propose that NE dynamically modulates Pavlovian conditioning and...
Article
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The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings...
Article
Generating appropriate defensive behaviors in the face of threat is essential to survival. Although many of these behaviors are ‘hard-wired’, they are also flexible. For example, Pavlovian fear conditioning generates learned defensive responses, such as conditioned freezing, that can be suppressed through extinction. The expression of extinguished...
Article
Inhibitory interneurons comprise a diverse subpopulation of cells that are critical to circuit function. How distinct inhibitory microcircuits control long-range projections remains poorly understood. A recent study by Lu and colleagues uncovered a unidirectional microcircuit of prefrontal chandelier cells that preferentially innervate and suppress...
Article
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Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including t...
Article
Input specificity is a fundamental property of long-term potentiation (LTP), but it is not known if learning is mediated by synapse-specific plasticity. Kim and Cho (2017) now show that fear conditioning is mediated by synapse-specific LTP in the amygdala, allowing animals to discriminate stimuli that predict threat from those that do not.
Article
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Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulati...
Article
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Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the e...
Article
Individuals respond differently to traumatic experiences including their propensity to develop post-traumatic stress disorder (PTSD). Understanding individual differences in PTSD vulnerability will allow the development of improved prevention and treatment options. Here, we characterized fear conditioning and extinction in rats selectively bred for...
Article
Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms in...
Chapter
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Article
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The medial prefrontal cortex (mPFC) plays a crucial role in emotional learning and memory in rodents and humans. While many studies suggest a differential role for the prelimbic (PL) and infralimbic (IL) subdivisions of mPFC, few have considered the relationship between neural activity in these two brain regions recorded simultaneously in behaving...
Article
Full-text available
Stress plays a critical role in the development and expression of many psychiatric disorders, and is a defining feature of post-traumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies, such as exposure therapy, aimed at limiting pathological fear. Here we examine emerging evidence that stress impairs recovery from...
Article
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The basolateral amygdala (BLA) is critical for encoding the value of stimuli. Beyeler et al. (2016) now show that distinct populations of BLA neurons, which are defined by their efferent targets, code reward and aversion. This arrangement promotes parallel processing of biologically relevant events. The basolateral amygdala (BLA) is critical for en...
Article
Anatomical disconnection of the ventral hippocampus (VH) and medial prefrontal cortex (mPFC) impairs the renewal of extinguished fear in rats. Here we examined whether subpopulations of neurons in the VH that project to the mPFC, including the prelimbic cortex (PL) and infralimbic cortex (IL), are selectively or differentially engaged by the renewa...
Article
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Emotional arousal can have a profound impact on various learning and memory processes. For example, unconditioned emotional stimuli (e.g., predator odor or anxiogenic drugs) enhance dorsolateral striatum (DLS)-dependent habit memory. These effects critically depend on a modulatory role of the basolateral complex of the amygdala (BLA). Recent work i...
Article
Posttraumatic stress disorder (PTSD) has been described as the only neuropsychiatric disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted individuals. PTSD is characterized by heightened noradrenergic signaling, as well as a resistance to extinction learning. Research aimed at promoting more...
Article
Full-text available
The hippocampal formation (HPC) and medial prefrontal cortex (mPFC) have well-established roles in memory encoding and retrieval. However, the mechanisms underlying interactions between the HPC and mPFC in achieving these functions is not fully understood. Considerable research supports the idea that a direct pathway from the HPC and subiculum to t...
Article
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Once acquired, a fearful memory can persist for a lifetime. Although learned fear can be extinguished, extinction memories are fragile. The resilience of fear memories to extinction may contribute to the maintenance of disorders of fear and anxiety, including post-traumatic stress disorder (PTSD). As such, considerable effort has been placed on und...
Article
Full-text available
Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been impl...
Article
In Anxious , renowned neuroscientist Joseph LeDoux tackles the neural origins of fear and anxiety with an eye to developing empirically informed treatments for anxiety disorders. In a significant departure from his earlier views on the neural underpinnings of fear, LeDoux carves the emotional brain into two parts: an evolutionarily old threat detec...
Article
Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spont...
Article
The extinction of conditioned fear is labile. For example, fear to an extinguished conditioned stimulus (CS) returns after presentation of an aversive stimulus ("reinstatement") or a change in context ("renewal"). Substantial research implicates the bed nucleus of the stria terminalis (BNST) in the stress-induced relapse of extinguished behaviors,...
Article
Aversive events can trigger relapse of extinguished fear memories, presenting a major challenge to the long-term efficacy of therapeutic interventions. Here, we examined factors regulating the relapse of extinguished fear after exposure of rats to a dangerous context. Rats received unsignaled shock in a distinct context ("dangerous" context) 24 h p...
Article
Anxiety, trauma and stress-related disorders are often characterized by a loss of context-appropriate emotional responding. The contextual retrieval of emotional memory involves hippocampal projections to the medial prefrontal cortex and amygdala; however the relative contribution of these projections is unclear. To address this question, we charac...
Chapter
The amygdala is a temporal lobe structure in the brain that is critical for aversive emotions, particularly fear. Studies of rats, mice, rabbits, non-human primates and humans indicate that nuclei within the amygdala are involved in the genesis of both innate and learned fears. Understanding the role of the amygdala in fear has led to progress in t...
Article
Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to inf...
Article
There is considerable interest, from both a basic and clinical standpoint, in gaining a greater understanding of how pharmaceutical or behavioral manipulations alter fear extinction in animals. Not only does fear extinction in rodents model exposure therapy in humans, where the latter is a cornerstone of behavioral intervention for anxiety disorder...
Article
Full-text available
After fear conditioning, presenting the conditioned stimulus (CS) alone yields a context-specific extinction memory; fear is suppressed in the extinction context, but renews in any other context. The context-dependence of extinction is mediated by a brain circuit consisting of the hippocampus, prefrontal cortex (PFC) and amygdala. In the present wo...
Article
The extinction of fear is believed to involve inhibitory processes in the amygdala. In this issue of Neuron, Trouche et al. (2013) show that basal amygdala neurons activated by fear conditioning are silenced by local inhibitory interneurons after extinction.