Induction of Fear Extinction with Hippocampal-Infralimbic BDNF

Peters, Jamie; Dieppa-Perea, Laura M.; Meléndez, Loyda M.; Quirk, Gregory J.

doi:10.1126/science.1186909

Cited by 428 publications

(463 citation statements)

References 27 publications

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“…Consistent with these findings, BDNF is reduced in the cerebrospinal fluid of patients with PTSD (Bonne et al, 2011). Interestingly, infusion of BDNF into the dorsal hippocampus can cause extinction of conditioned fear, which is blocked by inhibiting the function of BDNF in the medial prefrontal cortex (Peters et al, 2010), consistent with our findings of abnormal posterior hippocampal/ default-mode network connectivity and function in PTSD.…”

Section: A Default-mode Network-based Posterior Hippocampus Circuitrysupporting

confidence: 79%

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

Chen

Etkin

2013

Neuropsychopharmacol

191

178

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Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal defaultmode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting-state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task-based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders.

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Section: A Default-mode Network-based Posterior Hippocampus Circuitrysupporting

confidence: 79%

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

Chen

Etkin

2013

Neuropsychopharmacol

191

178

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“…Thus, E 2 may promote extinction through stimulation of MAPK cascades. Similarly, levels of brainderived neurotrophic factor are increased following both E 2 administration (Luine and Frankfurt 2012) and successful extinction (Peters et al 2010). Collectively, these findings suggest that E 2 acts to strengthen synaptic plasticity associated with extinction learning.…”

Section: Discussionmentioning

confidence: 57%

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

et al. 2013

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Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17b-estradiol (E 2 ) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E 2 treatment followed by 2 d of vehicle treatment, or were injected with E 2 daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E 2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E 2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E 2 -treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E 2 could rescue extinction in these rats, half were given daily E 2 treatment and half were given vehicle. E 2 -treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E 2 is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E 2 levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts.Gonadal hormones render women more susceptible than men to developing compulsive patterns of psychostimulant use. Natural fluctuations in levels of the primary ovarian hormones, estrogens and progesterone, account for this increased abuse liability. Higher levels of estrogens, and lower levels of progesterone, are associated with greater sensitivity to the euphorigenic properties of cocaine in women (Evans 2007). This increased sensitivity may contribute to why women, compared with men, start using cocaine regularly at a younger age (Chen and Kandel 2002), transition from use to abuse more quickly (McCance-Katz et al. 1999), experience greater craving in response to drug-associated cues (Robbins et al. 1999) and stress (Potenza et al. 2012;Waldrop et al. 2012), and exhibit more severe drug-seeking behavior upon relapse (Gallop et al. 2007). In contrast, more women than men remain abstinent after treatment (Weiss et al. 1997). Thus, women are both more susceptible to cocaine abuse and, paradoxically, more responsive to treatment.A substantial literature supports that estrogens mediate the enhancement of drug seeking observed in females (Febo et al. 2002;Larson et al. 2007;Segarra et al. 2010; Kerstetter and Kippin 2011), but little is known regarding the role of estrogens during treatment. Preclinically, treatment is modeled through ext...

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“…Extinction of conditioned fear is an active process requiring gene transcription and protein synthesis (25,26). Evidence suggests that BDNF is required for cued fear extinction, particularly in the amygdala-PFC-hippocampus circuits (55,56). However, the normal extinction of short-term cue fear in BDNF-KIV mice suggests that short-term extinction of cued memory does not require activity-dependent BDNF expression but may be dependent on constitutive BDNF (Fig.…”

Section: Discussionmentioning

confidence: 99%

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

Sakata

Martinowich²,

Woo

et al. 2013

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

119

131

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Activity-dependent gene transcription, including that of the brainderived neurotrophic factor (Bdnf) gene, has been implicated in various cognitive functions. We previously demonstrated that mutant mice with selective disruption of activity-dependent BDNF expression (BDNF-KIV mice) exhibit deficits in GABA-mediated inhibition in the prefrontal cortex (PFC). Here, we show that disruption of activity-dependent BDNF expression impairs BDNF-dependent late-phase long-term potentiation (L-LTP) in CA1, a site of hippocampal output to the PFC. Interestingly, early-phase LTP and conventional L-LTP induced by strong tetanic stimulation were completely normal in BDNF-KIV mice. In parallel, attenuation of activity-dependent BDNF expression significantly impairs spatial memory reversal and contextual memory extinction, two executive functions that require intact hippocampal-PFC circuitry. In contrast, spatial and contextual memory per se were not affected. Thus, activity-dependent BDNF expression in the hippocampus and PFC may contribute to cognitive and behavioral flexibility. These results suggest distinct roles for different forms of L-LTP and provide a link between activity-dependent BDNF expression and behavioral perseverance, a hallmark of several psychiatric disorders.

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Induction of Fear Extinction with Hippocampal-Infralimbic BDNF

Cited by 428 publications

References 27 publications

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

Hippocampal Network Connectivity and Activation Differentiates Post-Traumatic Stress Disorder From Generalized Anxiety Disorder

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

Role of activity-dependent BDNF expression in hippocampal–prefrontal cortical regulation of behavioral perseverance

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