Hippocampal and Prefrontal Projections to the Basal Amygdala Mediate Contextual Regulation of Fear after Extinction

Orsini, Caitlin A.; Kim, Jee Hyun; Knapska, Ewelina; Maren, Stephen

doi:10.1523/jneurosci.4095-11.2011

Cited by 279 publications

(299 citation statements)

References 47 publications

(66 reference statements)

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“…Because the vHIPP is the primary source of contextual information to the amygdala (15) and can influence La activity indirectly via its projections to the PL (28), it is conceivable that the vHIPP contributes to the context dependence of extinction through both direct and indirect projections to the La. Indeed, it has recently been shown that BA-projecting neurons in both the PL and HIPP are preferentially active during the renewal of fear to an extinguished CS and that disconnection of either the direct or indirect routes by which the HIPP projects to the BA impaired the renewal of fear memories after extinction (12).…”

Section: Discussionmentioning

confidence: 99%

“…There is also growing evidence for subregional differences within the PFC: the infralimbic (IL) and prelimbic (PL) cortices have opposite influences on fear expression, inhibiting and exciting amygdala output, respectively (9-11). Moreover, convergent inputs from both the PL and ventral HIPP (vHIPP) in the Ba mediate fear renewal (12). Recently, Herry et al (13) have shown that rapid transitions between behavioral states of low and high fear, evoked by fear extinction and its context-dependent renewal, respectively, can be triggered by a switch in the balance of activity between two distinct populations of Ba neurons, which appear to be integrated into discrete neuronal circuits differentially connected with the HIPP and PFC.…”

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confidence: 99%

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Functional anatomy of neural circuits regulating fear and extinction

Knapska¹,

Macias

Mikosz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

166

132

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The memory of fear extinction is context dependent: fear that is suppressed in one context readily renews in another. Understanding of the underlying neuronal circuits is, therefore, of considerable clinical relevance for anxiety disorders. Prefrontal cortical and hippocampal inputs to the amygdala have recently been shown to regulate the retrieval of fear memories, but the cellular organization of these projections remains unclear. By using anterograde tracing in a transgenic rat in which neurons express a dendriticallytargeted PSD-95:Venus fusion protein under the control of a c-fos promoter, we found that, during the retrieval of extinction memory, the dominant input to active neurons in the lateral amygdala was from the infralimbic cortex, whereas the retrieval of fear memory was associated with greater hippocampal and prelimbic inputs. This pattern of retrieval-related afferent input was absent in the central nucleus of the amygdala. Our data show functional anatomy of neural circuits regulating fear and extinction, providing a framework for therapeutic manipulations of these circuits.gene expression | hippocampus | prefrontal cortex | learning and memory T here is an increasing interest in the neural mechanisms underlying extinction of learned fear, in part because fear extinction is a useful model for exposure-based therapies for the treatment of human anxiety disorders, such as phobias and posttraumatic stress disorder (1). During fear extinction, a previously conditioned stimulus (CS) is repeatedly presented in the absence of the unconditioned stimulus (US), a procedure that induces a progressive decrease in the magnitude and probability of learned fear responses, including freezing behavior. However, extinction does not erase the original fear memory; rather, it promotes the formation of a new inhibitory memory that reduces fear to the CS (2). Extinguished fear is highly context dependent, insofar as CS presentation outside the extinction context results in the recovery of the previously conditioned fear response, a phenomenon known as fear renewal (3). The return of fear after extinction is a considerable challenge for the efficacy of exposure-based therapies (4). Therefore, identification of brain structures and neuronal circuits selectively implicated in extinction vs. renewal of fear is of great importance.Owing to substantial progress toward understanding the neural mechanisms underlying the context specificity of fear extinction, there is now a general consensus that, for auditory fear conditioning, extinction involves three main structures: the amygdala, hippocampus (HIPP), and prefrontal cortex (PFC) (2, 5-8). However, the neuronal interactions between these structures that underlie contextual retrieval of fear memory after extinction remain to be elucidated. This problem is further complicated by the fact that neither the amygdala nor the PFC is a homogeneous structure. Among the substructures of the amygdala, the central, basal, and lateral nuclei (Ce, Ba, and La, respectively) have been impl...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Functional anatomy of neural circuits regulating fear and extinction

Knapska¹,

Macias

Mikosz³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

166

132

View full text Add to dashboard Cite

show abstract

“…Infralimbic and prelimbic cortices have opposing roles in the expression of fear following extinction learning (Senn et al, 2014), which suggests that these reciprocal connections influence the outcome of fear and extinction learning. Moreover, inputs from the ventral hippocampus onto the BLA, either directly or indirectly through the prelimbic cortex, mediate contextual control of fear and fear renewal after extinction (Orsini et al, 2011).…”

Section: Neural Systems Involved In Fear Learningmentioning

confidence: 99%

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress

Perusini

Meyer

Long

et al. 2015

Neuropsychopharmacol

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Fear promotes adaptive responses to threats. However, when the level of fear is not proportional to the level of threat, maladaptive fear-related behaviors characteristic of anxiety disorders result. Post-traumatic stress disorder develops in response to a traumatic event, and patients often show sensitized reactions to mild stressors associated with the trauma. Stress-enhanced fear learning (SEFL) is a rodent model of this sensitized responding, in which exposure to a 15-shock stressor nonassociatively enhances subsequent fear conditioning training with only a single trial. We examined the role of corticosterone (CORT) in SEFL. Administration of the CORT synthesis blocker metyrapone prior to the stressor, but not at time points after, attenuated SEFL. Moreover, CORT co-administered with metyrapone rescued SEFL. However, CORT alone without the stressor was not sufficient to produce SEFL. In these same animals, we then looked for correlates of SEFL in terms of changes in excitatory receptor expression. Western blot analysis of the basolateral amygdala (BLA) revealed an increase in the GluA1 AMPA receptor subunit that correlated with SEFL. Thus, CORT is permissive to trauma-induced changes in BLA function.

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“…R. Soc. B 369: 20130160 fear renewal not only require an intact amygdala but are also hippocampus-dependent [42].…”

Section: (D) Lack Of Ophn1 Abolishes Presynaptic Long-term Potentiatimentioning

confidence: 99%

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

Khelfaoui

Gambino

Houbaert

et al. 2014

Phil. Trans. R. Soc. B

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Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.

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Hippocampal and Prefrontal Projections to the Basal Amygdala Mediate Contextual Regulation of Fear after Extinction

Cited by 279 publications

References 47 publications

Functional anatomy of neural circuits regulating fear and extinction

Functional anatomy of neural circuits regulating fear and extinction

Induction and Expression of Fear Sensitization Caused by Acute Traumatic Stress

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

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