Jasmeer P. Chhatwal

Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories

Brain-derived neurotrophic factor (BDNF) is known to play a critical role in the synaptic plasticity underlying the acquisition and/or consolidation of certain forms of memory. Additionally, a role has been suggested for neurotrophin function within the hippocampus in protection from anxiety and depressive disorders. Understanding the function of this important gene in adult animals has been limited however, because standard knockouts are confounded by gene effects during development. There are no BDNF receptor-specific pharmacological agents, and infusions of neuropeptides or antibodies have other significant limitations. In these studies, we injected a lentivirus expressing Cre recombinase bilaterally into the dorsal hippocampus in adult mice floxed at the BDNF locus to facilitate the site-specific deletion of the BDNF gene in adult animals. Significant decreases in BDNF mRNA expression are demonstrated in the hippocampi of lenti-Cre-infected animals compared with control lenti-GFP-infected animals. Behaviorally, there were no significant effects of BDNF deletion on locomotion or baseline anxiety measured with startle. In contrast, hippocampal-specific BDNF deletions impair novel object recognition and spatial learning as demonstrated with the Morris water maze. Although there were no effects on the acquisition or expression fear, animals with BDNF deletions show significantly reduced extinction of conditioned fear as measured both with fear-potentiated startle and freezing. These data suggest that the cognitive deficits and impairment in extinction of aversive memory found in depression and anxiety disorders may be directly related to decreased hippocampal BDNF.

Enhancing Cannabinoid Neurotransmission Augments the Extinction of Conditioned Fear

The endogenous cannabinoid (eCB) system represents a major therapeutic target for the treatment of a variety of anxiety-related disorders. A recent study has demonstrated that pharmacologic or genetic disruption of CB1-receptor-mediated neurotransmission decreases the extinction of conditioned fear in mice. Here, we examined whether CB1 blockade would similarly disrupt extinction in rats, using fear-potentiated startle as a measure of conditioned fear. We also examined whether pharmacologic enhancement of CB1 activation would lead to enhancements in extinction. Our results indicate that systemic administration of the CB1 antagonist rimonabant (SR141716A) prior to extinction training led to significant, dose-dependent decreases in extinction. While the administration of the CB1 agonist WIN 55,212-2 did not appear to affect extinction, administration of AM404, an inhibitor of eCB breakdown and reuptake, led to dose-dependent enhancements in extinction. In addition to showing decreased fear 1 and 24 h after extinction training, AM404-treated animals showed decreased shock-induced reinstatement of fear. Control experiments demonstrated that the effects of AM404 could not be attributed to alterations in the expression of conditioned fear, locomotion, shock reactivity, or baseline startle, as these parameters seemed unchanged by AM404. Furthermore, coadministration of rimonabant with AM404 blocked this enhancement of extinction, suggesting that AM404 was acting to increase CB1 receptor activation during extinction training. These results demonstrate that the eCB system can be modulated to enhance emotional learning, and suggest that eCB modulators may be therapeutically useful as adjuncts for exposure-based psychotherapies such as those used to treat Post-Traumatic Stress Disorder and other anxiety disorders.

Tau positron emission tomographic imaging in aging and early Alzheimer disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

Tau PET imaging in aging and early Alzheimer's disease

Detection of focal brain tau deposition during life could greatly facilitate accurate diagnosis of Alzheimer disease (AD), staging and monitoring of disease progression, and development of disease‐modifying therapies.

Amygdala BDNF signaling is required for consolidation but not encoding of extinction

Brain-derived neurotrophic factor (BDNF) acting through the tyrosine kinase B receptor (TrkB) is thought to be a critical mediator of learning. As there are no available selective antagonists of TrkB, we used a lentivirus encoding a dominant-negative TrkB (TrkB.t1) to antagonize BDNF signaling during extinction of conditioned fear. Whereas TrkB.t1-infected rats showed normal within-session extinction, their retention of extinction was impaired, suggesting that amygdala TrkB activation is required for the consolidation of stable extinction memories.

Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction.

Both the acquisition and extinction of conditioned fear appear to require the basolateral amygdala (BLA). Because these two forms of learning have opposing effects on the expression of conditioned fear, we hypothesized that they may modulate GABAergic tone differentially within the BLA. Previously, we reported that gene expression for the GABAA receptor clustering protein gephyrin was significantly downregulated in the BLA after fear acquisition (Ressler et al., 2002). Here we demonstrate an analogous decrease in BLA gephyrin protein levels, together with a decrease in the surface expression of GABAA receptors in the BLA after fear acquisition, as evidenced by decreased binding of H3-flunitrazepam. In marked contrast, gephyrin mRNA and protein levels in the BLA significantly increased after extinction training, as did H3-flunitrazepam binding. These results implicate the protein gephyrin in both fear acquisition and extinction and suggest that the modulation of gephyrin and GABAA receptor expression in the BLA may play a role in the experience-dependent plasticity underlying both of these types of learning. Furthermore, these results demonstrate that physiologically relevant, dynamic alterations of GABAergic synapses occur during the consolidation phase of BLA-dependent learning and may interact with previously described alterations in glutamatergic transmission to initiate and stabilize memory formation in vivo.

Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy.

SummaryA great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or “unlearning” of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.

Impaired default network functional connectivity in autosomal dominant Alzheimer disease

Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participants estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.

Functional Interactions between Endocannabinoid and CCK Neurotransmitter Systems May Be Critical for Extinction Learning

The endocannabinoid system and the cannabinoid type 1 receptor (CB1R) are required for the extinction of conditioned fear. CB1 antagonists have been shown to prevent extinction when delivered both systemically and within the amygdala. Anatomical studies suggest that CB1Rs in the basolateral amygdala (BLA) are expressed on GABAergic interneurons expressing the anxiogenic peptide cholecystokinin (CCK). Pre-synaptic CB1Rs inhibit neurotransmitter release, suggesting that CB1R activation during extinction may decrease CCK peptide release as well as GABA release. Thus, we examined whether extinction involves the CB1R modulation of CCK2 receptor activation. We found that intracerebroventricular administration of the CCK2 agonist pentagastrin dose-dependently impaired extinction of conditioned fear. Systemic administration of a CB1 antagonist, rimonabant (SR141716), also potently inhibited extinction learning. This effect was ameliorated with systemic administration of a CCK2 antagonist, CR2945. Furthermore, the extinction blockade by systemic SR141716 was reversed with intra-BLA, but not intrastriatal, infusion of CR2945. Lastly, as extinction usually leads to an increase in Akt phosphorylation, a biochemical effect antagonized by systemic CB1 antagonist treatment, we examined whether CR2945 co-administration would increase extinction-induced p-Akt levels. We observed that extinction-trained animals showed increased Akt phosphorylation following extinction, CB1 antagonist-treated animals showed p-Akt levels similar to those of non-extinction trained animals, and co-administration of CR2945 with SR141716 led to levels of p-Akt similar to those of vehicle-treated, extinction-trained controls. Together, these data suggest that interactions between the endocannabinoid and CCKergic transmitter systems may underlie the process of extinction of conditioned fear.

Reduced prefrontal cortical dopamine, but not acetylcholine, release in vivo after repeated, intermittent phencyclidine administration to rats

Subchronic administration of phencyclidine to rats or monkeys produces prefrontal cortical cognitive dysfunction, as well as reduced frontal cortical dopamine utilization. In the current study, the effects of subchronic exposure to phencyclidine on dopamine and acetylcholine release in the prefrontal cortex were assessed, using in vivo microdialysis in conscious rats. Subchronic exposure to phencyclidine (5 mg/kg twice daily for 7 days) reduced both basal extracellular concentrations of dopamine as well as the increase in dopamine release produced by an acute phencyclidine challenge. The increase in dopamine release induced by a high potassium concentration in the perfusate tended to be reduced after subchronic phencyclidine treatment, while basal and evoked acetylcholine release was unaffected. These data demonstrate that altered dopamine turnover in subjects after subchronic exposure to phencyclidine is directly reflective of reduced release, and as such, represents a functionally relevant phenomenon.