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Publications
Publications (133)
Stressful experiences, both physical and psychological, that are overwhelming (i.e., inescapable and unpredictable), can measurably affect subsequent neuronal properties and cognitive functioning of the hippocampus. At the cellular level, stress has been shown to alter hippocampal synaptic plasticity, spike and local field potential activity, dendr...
The medial prefrontal cortex (mPFC) has been implicated in regulating resistance to the effects of acute uncontrollable stress. We previously showed that mPFC-lesioned animals exhibit impaired object recognition memory after acute exposure to a brief stress that had no effect in normal animals. Here, we used designer receptors exclusively activated...
Pavlovian fear conditioning, which offers the advantage of simplicity in both the control of conditional and unconditional stimuli (CS, US) presentation and the analysis of specific conditional and unconditional responses (CR, UR) in a controlled laboratory setting, has been the standard model in basic and translational fear research. Despite 100 y...
Significance
Although exploitation of labor in groups is a hallmark of social animals, its underlying neural mechanisms remain unknown. We explored this matter using a “social problem” paradigm in which one rat, the “worker,” predominantly performed lever-pressing for food delivery while the other “parasitic” rats consumed nearly all delivered food...
Pavlovian fear conditioning, which offers the advantage of simplicity in both the control of conditioned and unconditioned stimuli (CS, US) presentation and the analysis of specific conditioned and unconditioned responses (CR, UR) in a controlled laboratory setting, has been the standard model in basic and translational fear research. Despite 100 y...
[This corrects the article DOI: 10.3389/fnbeh.2020.594568.].
Basic research of fear and anxiety in rodents has historically utilized a limited set of behavioral paradigms, for example, Pavlovian (classical) fear conditioning, the elevated plus-maze, or inhibitory (passive) avoidance. These traditional paradigms measure a limited selection of variables over a short duration, providing only a "snapshot" of fea...
The medial prefrontal cortex (mPFC) is thought to exert inhibitory control over stress-induced activation of the amygdala and neurocognitive effects. As evidence to support this, we examined how exposure to either a brief or prolonged stress affected on amygdalar c-Fos levels and recognition memory of animals with mPFC chemical lesions. mPFC-lesion...
Adverse stress effects on the hippocampal memory system are generally thought to be due to the high level of circulating glucocorticoids directly modifying the properties of hippocampal neurons and, accordingly, the results should be reproducible with exogenous administration of cortisol in humans and corticosterone in rodents. However, glucocortic...
Rodents in the wild are under nearly constant threat of aerial predation and thus have evolved adaptive innate defensive behaviors, such as freezing or fleeing, in response to a perceived looming threat. Here we employed an ethologically relevant paradigm to study innate fear of aerial predators in male and female rats during a goal-oriented task....
Fear is considered an integral part of the brain's defensive mechanism that evolved to protect animals and humans from predation and other ecological threats. Hence, it is logical to study fear from the perspective of antipredator-survival behaviors and circuits by sampling a range of threatening situations that organisms are likely to encounter in...
Background:
The bursting pattern of thalamocortical (TC) pathway dampens nociception. Whether brain stimulation mimicking endogenous patterns can engage similar sensory gating processes in the cortex and reduce nociceptive behaviors remains uninvestigated.
Objective:
We investigated the role of cortical parvalbumin expressing (PV) interneurons w...
Predation is considered a major selective pressure in the evolution of fear, but the neurophysiology of predator-induced fear is unknown. We simultaneously recorded lateral amygdala (LA) and prelimbic (PL) area neuronal activities as rats exited a safe nest to search for food in an open space before, during, and after encountering a “predator” robo...
The scientific understanding of fear and anxiety—in both normal and pathological forms—is presently limited by a predominance of studies that use male animals and Pavlovian fear conditioning-centered paradigms that restrict and assess specific behaviors (e.g., freezing) over brief sampling periods and overlook the broader contributions of the spati...
Study objectives:
Sleep is important for consolidation of hippocampus-dependent memories. It is hypothesized that the temporal sequence of nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep is critical for the weakening of nonadaptive memories and the subsequent transfer of memories temporarily stored in the hippocampus to more...
Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem...
Fear is an innate, behavioral–motivational system that allows humans and animals to rapidly enact specific defensive behaviors in response to stimuli that the system, either through natural selection or learning, has come to recognize as potentially dangerous. The fear system likely evolved due to the reproductive success it conferred animals that...
The hippocampus is vulnerable to uncontrollable stress and is enriched with oxytocin receptors, but their interactive influences on hippocampal functioning are unknown. This study aimed to determine the effects of intranasal oxytocin administration on stress-induced alterations in synaptic plasticity and spatial memory in male rats. While vehicle-a...
Chronic uncontrollable stress has been shown to produce various physiological alterations and impair mnemonic functions in the rodent hippocampus. Impacts on neuronal activities, however, have not been well investigated. The present study examined dorsal CA1 place cells to elucidate the computational changes associated with chronic stress effects o...
Virtually all animals have endogenous clock mechanisms that "entrain" to the light-dark (LD) cycle and synchronize psychophysiological functions to optimal times for exploring resources and avoiding dangers in the environment. Such circadian rhythms are vital to human mental health, but it is unknown whether circadian rhythms "entrained" to the LD...
Uncontrollable stress has been recognized to influence the hippocampus at various levels of analysis. Behaviorally, human and animal studies have found that stress generally impairs various hippocampal-dependent memory tasks. Neurally, animal studies have revealed that stress alters ensuing synaptic plasticity and firing properties of hippocampal n...
Prey are relentlessly faced with a series of survival problems to solve. One enduring problem is predation, where the prey's answers rely on the complex interaction between actions cultivated during its life course and defense reactions passed down by descendants. To understand the proximate neural responses to analogous threats, affective neurosci...
Fear is an adaptive mechanism evolved to influence the primal decisions of foragers in "approach resource-avoid predator" conflicts [1-3]. To survive and reproduce, animals must attain the basic needs (food, water, shelter, and mate) while avoiding the ultimate cost of predation [4]. Consistent with this view, ecological studies have found that pre...
Considerable evidence seems to show that emotional and reflex reactions to feared situations are mediated by the amygdala. It might therefore seem plausible to expect that amygdala-coded fear should also influence decisions when animals make choices about instrumental actions. However, there is not good evidence of this. In particular, it appears,...
It is now well-accepted that uncontrollable (i.e., acute traumatic, prolonged) stress can have lingering effects on the hippocampus. At the behavioral level, evidence from human and animal studies indicates that stress generally impedes performance in a variety of hippocampal-dependent memory tasks. At the neural level, animal studies have shown th...
The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fear-conditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hen...
Previous research has demonstrated that naltrexone (NTX) enhances acquisition of aversive excitatory Pavlovian conditioning. Both the conditional opponent theory (Schull, 1979) and the perceived intensity hypothesis (Fanselow, 1981; Young & Fanselow, 1992) accurately predict this result. Nevertheless, these two models make different predictions abo...
An organism's chances for survival are greatly impacted by its ability to learn from previous experience and form memories to modify future behaviour. The search for the engram, the physical trace of a memory in the brain, has resulted in a wealth of data beginning to uncover how memories are stored at the molecular-cellular level. Despite terminol...
Stress is a biologically ubiquitous factor that, when perceived uncontrollable by humans and animals, can have lingering adverse effects on brain and cognitive functions. We have previously reported that rats that experienced inescapable-unpredictable stress subsequently exhibited decreased stability of firing rates of place cells in the CA1 hippoc...
Much research shows that early life manipulations have enduring behavioral, neural, and hormonal effects. However, findings of learning and memory performance vary widely across studies. We reviewed studies in which pre-weaning rat pups were exposed to stressors and tested on learning and memory tasks in adulthood. Tasks were classified as aversive...
Modern views on learning and memory accept the notion of biological constraints-that the formation of association is not uniform across all stimuli. Yet cellular evidence of the encoding of selective associations is lacking. Here, conditioned stimuli (CSs) and unconditioned stimuli (USs) commonly employed in two basic associative learning paradigms...
Three experiments examined the role of the dorsal hippocampus (dHIPP) in occasion setting with diffuse contextual and discrete light stimuli serving as occasion setters in classical fear conditioning with rats. Both sham-operated and dHIPP-lesioned animals readily learned a L→T+, T- serial feature-positive discrimination in which a light (L) "set t...
Serotonin 1B (5-HT(1B)) autoreceptors regulate release of serotonin from terminals of dorsal raphe nucleus (DRN) projections. Expression of 5-HT(1B) in the DRN inversely correlates with behavioral measures of emotion, and viral-mediated overexpression of 5-HT(1B) receptors in the middle DRN inversely reduces measures of fear and anxiety in unstress...
The modern views on associative learning and memory have been profoundly influenced by the classical conditioning phenomenon of blocking. Specifically, blocking revealed that the informational relationship, rather than the temporal relationship, between stimuli is essential for the formation of associative constructs in animals and humans. Empirica...
The time course of USV emitted by individual receiver rats during three unsignaled shocks (represented by filled triangles) and their subsequent freezing level during the pair-testing (A). Eight rats were divided into USV-footshock ‘paired’ and USV-footshock ‘unpaired’ groups depending on whether their USV preceded and overlapped with footshock(s)....
Mean percentage (± SEM) freezing (A) and USV (B) displayed by SFC rats during auditory fear conditioning (10 tone-footshock pairings), and mean percentage freezing (C) and USV (D) by RFE rats during fear experience (3 unsignaled footshocks.
(TIF)
Mean percentage (± SEM) freezing during pair-testing by SFC and RN rats that were pair-housed for either 1 week or 3 weeks prior to the experiment. There was no effect of the duration of pair-housing.
(TIF)
Mean percentage (± SEM) freezing (A) and USV (B) displayed during first 3-min period of the tone testing on day 3 by SFC animals injected with lidocaine in their MGNs (SFC-LI) and when re-tested in drug-free state (SFC-no drug) on day 4.
(TIF)
Social alarm calls alert animals to potential danger and thereby promote group survival. Adult laboratory rats in distress emit 22-kHz ultrasonic vocalization (USV) calls, but the question of whether these USV calls directly elicit defensive behavior in conspecifics is unresolved.
The present study investigated, in pair-housed male rats, whether an...
In a natural environment, foragers constantly face the risk of encountering predators. Fear is a defensive mechanism evolved to protect animals from danger by balancing the animals' needs for primary resources with the risk of predation, and the amygdala is implicated in mediating fear responses. However, the functions of fear and amygdala in forag...
Extensive fear extinction research is guided by the view that there are structures in the brain that develop inhibitory control over the expression of conditioned fear memories. While the medial prefrontal cortex has recently captured attention as the locus of plasticity essential for extinction of conditioned fear, the auditory cortex is another p...
Stress is a biologically significant social-environmental factor that plays a pervasive role in influencing human and animal behaviors. While stress effects on various types of memory are well characterized, its effects on other cognitive functions are relatively unknown. Here, we investigated the effects of acute, uncontrollable stress on subseque...
Strain and sex differences in fear conditioning were investigated in two commonly used laboratory rats: Sprague Dawleys and Long-Evans. Twenty-two kHz ultrasonic vocalization (USV) distress calls and freezing behavior were used to measure fear responses to contextual and auditory conditioned stimuli (CSs), which were previously paired with a footsh...
The notion of uncontrollable stress causing reduced hippocampal size remains controversial in the posttraumatic stress disorder literature, because human studies cannot discern the causality of effect. Here, we addressed this issue by using structural magnetic resonance imaging in rats to measure the hippocampus and other brain regions before and a...
The conditioned eyeblink response (CR) in rabbits is lateralized to the eye targeted by the unconditioned stimulus (US). However, a contralateral component has been reported during concurrent discriminative conditioning of the two eyes. The authors investigated CRs produced by both eyes during conditioning with 2 different interstimulus intervals (...
Treatment with MK801 prior to conditioning reduces post-shock freezing and abolishes learning. (A) Freezing behavior during training. Both saline-treated and MK801-treated groups reacted vigorously to footshock US presentation, but only saline animals showed reliable postshock freezing (average freezing over 4 min post shock period indicated by gre...
Representative images of brain sections analyzed.(A) A schematic drawing of a coronal slice at −3.12 mm from bregma (modified from Paxinos and Watson, 1997). (B) A representative micrograph of a 20 µm slice containing sampled regions of BLA and CA1, CA3, and DG subregions of dorsal hippocampus. All whole neurons within the demarcated regions were s...
Stress influences various types of memory, but its effects on other cognitive functions are relatively unknown. We investigated the effects of uncontrollable stress on subsequent decision-making in rats, using a computer vision-based water foraging choice task. Stress impaired the animals' ability to bias their responses toward the larger reward wh...
Associative conditioning is a ubiquitous form of learning throughout the animal kingdom and fear conditioning is one of the most widely researched models for studying its neurobiological basis. Fear conditioning is also considered a model system for understanding phobias and anxiety disorders. A fundamental issue in fear conditioning regards the ex...
In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the eye to which the unconditioned stimulus (US) has been directed. However, the initial conditioning of one eye can facilitate subsequent conditioning of the other eye, a phenomenon known as the intereye transfer (IET) effect. Because a conditioned emotional...
Both the medial prefrontal cortex (mPFC) and hippocampus are implicated in working memory tasks in rodents. Specifically, it has been hypothesized that the mPFC is primarily engaged in the temporary storage and processing of information lasting from a subsecond to several seconds, while the hippocampal function becomes more critical as the working...
Neuropsychological and neuroimaging studies in humans have shown that the prefrontal cortex (PFC) is involved in long-term memory functioning. In general, the participation of the PFC in long-term memory has been attributed to its role in executive control rather than information storage. Accumulating data from recent animal studies, however, sugge...
Acute, inescapable, and unpredictable stress can profoundly modify brain and cognition in humans and animals. The present study investigated the ensuing effects of 2-h variable “audiogenic” stress on three related levels of hippocampal functions in rats: long-term potentiation, place cell activity, and spatial memory. In agreement with prior findin...
It is now well documented that both increased and decreased stress responses can profoundly affect cognition and behavior. This mini review presents possible neural mechanisms subserving stress effects on memory and aggression, particularly focusing on glucocorticoid (GC) hyper- and hypofunction. First, uncontrollable stress impedes hippocampal mem...
Early life events have profound consequences. Our research demonstrates that the early life stress of neonatal isolation (1-h individual isolation on postnatal days 2-9) in rats has immediate and enduring neural and behavioral effects. Recently, we showed neonatal isolation impaired hippocampal-dependent context conditioned fear in adult rats. We n...
We demonstrated that early life manipulations (neonatal isolation, neonatal handling, maternal separation) impaired fear conditioning in adult rats [Kosten, T.A., Miserendino, M.J.D., Bombace, J.C., Lee, H.J., Kim, J.J., 2005. Sex-selective effects of neonatal isolation on fear conditioning and foot shock sensitivity. Behav. Brain Res. 157, 235-244...
Current thinking about how memories are stored in the brain has been profoundly influenced by Donald O. Hebb's cell assembly hypothesis, which posits that (1) learning produces a stable alteration in patterns of connectivity among repeatedly coactivated neurons, and (2) memory retrieval involves reactivation of those altered patterns of connectivit...
The benchmark test for prefrontal cortex (PFC)-mediated working memory in rodents is a delayed alternation task utilizing variations of T-maze or Figure-8 maze, which requires the animals to make specific arm entry responses for reward. In this task, however, manual procedures involved in shaping target behavior, imposing delays between trials and...
The neural substrates of fear conditioning in rats have been well characterized, with converging lines of evidence indicating that conditioned stimulus (CS) and unconditioned stimulus (US) information form a CS-US association in the amygdala. Auditory CS information can reach the amygdala via two routes: a direct thalamo-amygdala pathway, and an in...
Pavlovian contextual fear conditioning occurs when an aversive unconditional stimulus (US), such as a footshock, is presented to a rat shortly after it is placed in an experimental context. Contextual fear conditioning does not occur when the shock is presented immediately upon placement of the rat in the novel chamber. In the present study, the au...
We demonstrated that neonatal isolation (1-h pup isolation; postnatal days 2-9) impairs context-induced fear conditioning in adult male rats and tends to enhance this effect and foot shock sensitivity in females. In this study, we examine the effects of brief (i.e., handling; 15 min) and prolonged (3 h) maternal separations (postnatal days 1-21) on...
It is now well-documented that exposures to uncontrollable (inescapable and unpredictable) stress in adulthood can have profound effects on brain and behavior. Converging lines of evidence from human and animal studies indicate that stress interferes with subsequent performances on a variety of hippocampal-dependent memory tasks. Animal studies fur...
Pavlovian or classical fear conditioning is recognized as a model system to investigate the neurobiological mechanisms of learning and memory in the mammalian brain and to understand the root of fear-related disorders in humans. In recent decades, important progress has been made in delineating the essential neural circuitry and cellular-molecular...
Electrolytic lesions to the amygdala, a limbic structure implicated in stress-related behaviors and memory modulation, have been shown to prevent stress-induced impairments of hippocampal long-term potentiation (LTP) and spatial memory in rats. The present study investigated the role of intrinsic amygdalar neurons in mediating stress effects on the...
Our previous work demonstrates enduring effects of the early life stress of neonatal isolation (ISO). ISO facilitates appetitive response learning in adult female, but not male rats, and enhances corticosterone levels and stress responsivity in infant and juvenile rats of both sexes. Corticosterone acts at brain areas such as hippocampus that are r...
Modern understanding of stress stems from classic work in the 1930s by Hans Selye, who developed the notion of the general
adaptation syndrome (Selye, 1936). Selye posited that the body shows a common, integrated set of responses in an attempt to adapt to many different kinds
of stress. Until his work, many scientists viewed different kinds of stre...
In the fear conditioning literature, it is generally hypothesized that neurons in the basolateral amygdalar complex (BLA) (lateral and basal nuclei) support the formation of conditioned fear memory and project to neurons in the central nucleus (CeA) for the expression of conditioned fear responses. According to this serial processing-transmission v...
Eyeblink conditioning has been hypothesized to engage two successive stages of nonspecific emotional (fear) and specific musculature (eyelid) learning, during which the nonspecific component influences the acquisition of the specific component. Here we test this notion by investigating the relative contributions of the cerebellum, the amygdala, and...
The relative contribution of left and right amygdalae in the acquisition and retention of fear conditioning was investigated in rats. Pretraining bilateral electrolytic lesions blocked the acquisition of conditioned fear to tone and context, whereas unilateral lesions induced partial impairments with no left-right amygdala differences. In contrast,...
Administration of muscarinic cholinergic antagonists such as scopolamine impairs the acquisition of contextual fear conditioning, but the role of the basal forebrain (BF) cholinergic system in consolidation is unclear. To test the hypothesis that BF cholinergic neurons are critical for acquisition and consolidation of fear conditioning, male Spragu...
Stress is a biologically significant factor that, by altering brain cell properties, can disturb cognitive processes such as learning and memory, and consequently limit the quality of human life. Extensive rodent and human research has shown that the hippocampus is not only crucially involved in memory formation, but is also highly sensitive to str...