Memories Of Fear Download 3gp Movie Fix
Fonda Boulay
Fear memory is the best-studied form of memory. It was thoroughly investigated in the past 60 years mostly using two classical conditioning procedures (contextual fear conditioning and fear conditioning to a tone) and one instrumental procedure (one-trial inhibitory avoidance). Fear memory is formed in the hippocampus (contextual conditioning and inhibitory avoidance), in the basolateral amygdala (inhibitory avoidance), and in the lateral amygdala (conditioning to a tone). The circuitry involves, in addition, the pre- and infralimbic ventromedial prefrontal cortex, the central amygdala subnuclei, and the dentate gyrus. Fear learning models, notably inhibitory avoidance, have also been very useful for the analysis of the biochemical mechanisms of memory consolidation as a whole. These studies have capitalized on in vitro observations on long-term potentiation and other kinds of plasticity. The effect of a very large number of drugs on fear learning has been intensively studied, often as a prelude to the investigation of effects on anxiety. The extinction of fear learning involves to an extent a reversal of the flow of information in the mentioned structures and is used in the therapy of posttraumatic stress disorder and fear memories in general.
The brain uses distinct mechanisms to store recent versus remote fear memories. Previous studies have suggested that while the initial formation of fear memory involves the hippocampus, it progressively matures with time and becomes less dependent on the hippocampus. Much research now explains how recent fear memory is stored, but how the brain consolidates remote fear memories is not well understood.
In the experiments, the mice received an aversive stimulus in an environment called a context. They learned to associate the aversive stimulus with the context. When exposed to the same context a month later, the mice froze in response, indicating they could recall remote fear memories. The researchers showed that connections (synapses) between memory neurons in the PFC, termed prefrontal memory circuits, were gradually strengthened with time after fear learning, and such strengthening helped the PFC permanently store remote fear memories.
Next, to extinguish the remote fear memory in the mice, the researchers repeatedly exposed the mice to the same fear-predictive context but without the aversive stimulus. The result was a reduced fear response to the context.
The findings suggest that during extinction training, the engram cells associated with the fear memory are suppressed and a second set of engram cells associated with the extinction memory are activated. During the spontaneous recovery of fear, the engram cells associated with the fear memory become more active than the engram cells associated with the extinction memory.
Together, these results suggest that in mice, fear acquisition and fear extinction recruit different groups of engram cells in the dentate gyrus and that interaction between these two groups of cells might be involved in fear recovery following extinction learning. Fear relapse is a challenge for successful exposure therapies. These findings point to brain mechanisms that could be explored as potential therapeutic targets for fear-associated behaviors in humans.
While persistence of fear memories is essential for survival, a failure to inhibit fear in response to harmless stimuli is a feature of anxiety disorders. Extinction training only temporarily suppresses fear memory recovery in adults, but it is highly effective in juvenile rodents. Maturation of GABAergic circuits, in particular of parvalbumin-positive (PV+) cells, restricts plasticity in the adult brain, thus reducing PV+ cell maturation could promote the suppression of fear memories following extinction training in adults. Epigenetic modifications such as histone acetylation control gene accessibility for transcription and help couple synaptic activity to changes in gene expression. Histone deacetylase 2 (Hdac2), in particular, restrains both structural and functional synaptic plasticity. However, whether and how Hdac2 controls the maturation of postnatal PV+ cells is not well understood. Here, we show that PV+- cell specific Hdac2 deletion limits spontaneous fear memory recovery in adult mice, while enhancing PV+ cell bouton remodeling and reducing perineuronal net aggregation around PV+ cells in prefrontal cortex and basolateral amygdala. Prefrontal cortex PV+ cells lacking Hdac2, show reduced expression of Acan, a critical perineuronal net component, which is rescued by Hdac2 re-expression. Pharmacological inhibition of Hdac2 before extinction training is sufficient to reduce both spontaneous fear memory recovery and Acan expression in wild-type adult mice, while these effects are occluded in PV+-cell specific Hdac2 conditional knockout mice. Finally, a brief knock-down of Acan expression mediated by intravenous siRNA delivery before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear recovery in wild-type mice. Altogether, these data suggest that controlled manipulation of PV+ cells by targeting Hdac2 activity, or the expression of its downstream effector Acan, promotes the long-term efficacy of extinction training in adults.
Anxiety and trauma-related disorders are associated with a huge socioeconomic burden, given the limited treatment options available [1]. Certain anxiety disorders are characterized by abnormally persistent emotional memories of fear-related stimuli, and impaired inhibition of learned fear is a feature in post-traumatic stress disorder (PTSD), anxiety disorders and phobias [2]. In rodents, pairing a neutral tone (conditioned stimulus, CS) with an aversive foot shock (unconditioned stimulus, US) leads to the formation of a robust fear memory that can last an entire lifetime [3]. The reduction of fear responses through fear extinction learning is at the heart of clinical exposure psychotherapies applied in the case of PTSD [4, 5]. In adults, extinction learning, or the gradual decrease of behavioral response to a CS that occurs when the stimulus is presented without reinforcement (e.g., without the aversive foot shock), is neither robust nor permanent since conditioned fear responses can recover spontaneously with the passage of time; in other words, extinction learning is unstable in adults [3, 6, 7]. Strategies aimed at enhancing the ability to inhibit responses to associations that are no longer relevant may have strong therapeutic value. Several studies suggested that the maturation of GABAergic neurotransmission contributes to the increased spontaneous recovery of fear memory following extinction learning in adults [8, 9]. Therefore, modulating GABAergic function is an attractive target to reduce spontaneous recovery of fear memories with time after extinction training in adults. However, global or prolonged reduction of GABAergic drive can generate undesirable effects such as epileptic activity. Therefore, ideal approaches targeting GABAergic transmission to foster adult brain plasticity need to be both cell type-specific and temporally controlled.
Amongst the different GABAergic interneuron types, reducing parvalbumin-expressing (PV+) interneuron activity or connectivity is sufficient to reinstate heightened plasticity in adult sensory cortices [10,11,12,13]. Recent studies showed that PV+ cells also play a role in fear memory extinction. First, fear responses during extinction learning are increased by chemogenetic activation of PV+ cells in the medial prefrontal cortex [14]. Second, extinction training induces remodeling of perisomatic PV+ synapses around excitatory neurons that were previously activated during fear conditioning in the basolateral amygdala (BLA) [15]. Third, PV+ cell-specific deletion of Nogo Receptor 1, a neuronal receptor for myelin-associated growth inhibitors [16], enhances BLA PV+ synapse remodeling and reduces the spontaneous recovery of fear memory after extinction training [17]. Fourth, fear extinction weakens the functional outputs of PV+ cells to pyramidal neurons in medial prefrontal cortex [14]. All together, these data suggest that GABAergic PV+ synapse remodeling, an activity-regulated process [18,19,20], may be implicated in extinction learning and long-term spontaneous recovery of fear memories.
Transcriptional mechanisms coupling synaptic activity to changes in gene expression drive cellular processes that mediate behavioral adaptations [21]. Accessibility of the chromatin to activate these transcriptional programs is modulated by changes in the state of histone acetylation of chromatin. In particular, blocking endogenous histone deacetylases (Hdacs) promotes both structural and functional synaptic plasticity processes [22, 23] that are required to modify behavior and improve performance during learning. Accordingly, administration of pan-Hdac inhibitors in adult mice reactivates visual cortical plasticity [24] and enhances extinction learning [25]. Several studies have shown that, of the many Hdacs expressed in the mammalian brain, Hdac2 plays a critical role in fear learning and memory [22, 23, 26]. A recent study showed that PV+ cell-specific deletion of Hdac2 was sufficient to decrease evoked IPSC and increase long-term depression in layer 2-3 of adult visual cortex [27], suggesting that deletion of Hdac2 in PV+ cells induced juvenile-like phenotypes both in inhibition and cortical plasticity. Therefore, manipulating Hdac2 expression in PV+ cells is an effective strategy to reduce their inhibitory output. Whether this would be sufficient to attenuate the recovery of fear memories after extinction training in adults is unknown.
PV+ interneurons are the only cortical cell type surrounded by perineuronal nets (PNNs), which are lattice-like aggregates of chondroitin sulfate proteoglycans-containing extracellular matrix [20]. The percentage of PV+ interneurons enwrapped by PNN increases during development in different brain regions, including those involved in fear memory formation and extinction [28]. Recent evidences show that PNNs stabilize afferent synaptic contacts onto mature cortical PV+ cells, thus limiting their plasticity [20, 29, 30]. Indeed, degradation of PNNs in adult BLA promotes fear memory erasure [28], a phenomena observed only in younger animals [8, 28, 31]. PNNs are dynamic structures, comprising of numerous structural components and remodeled by metalloproteases [32]. Whether the expression of distinct PNN components is controlled by epigenetic regulation specifically in PV+ cells, in turn modulating their role in cortical plasticity, is unknown.
dd2b598166