Caloric Restriction Enhances Fear Extinction Learning in Mice (original) (raw)
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Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit
Neuropsychopharmacology, 2015
Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feedforward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders.
Pharmacology Biochemistry and Behavior, 2007
A history of dieting is common in individuals suffering from eating disorders for which depression and mood disturbances are also comorbid. We investigated the effect of a history of caloric restriction (HCR) in rats that involved cyclic food restriction and refeeding with varying levels of access to palatable food (PF) on: 1) responses to the SSRI, fluoxetine; 2) monoamine levels in brain regions central to the control of feeding, reward, and mood regulation; and 3) behavioral tests of anxiety and depression. HCR coupled with intermittent but not daily access to PF exaggerated rats' anorectic response to fluoxetine (p<0.05); was associated with a significant 71% and 58% reduction of 5-HT and dopamine, respectively, in the medial prefrontal cortex; and induced behaviors consistent with models of depression. HCR, irrespective of access to PF, abolished the strong association between 5-HT and dopamine turnover in the nucleus accumbens in control rats (r =0.71 vs. -0.06, p<0.01). Access to PF, irrespective of HCR, reduced hypothalamic dopamine. Together, these findings suggest that a history of frequent food restriction-induced weight fluctuation imposes neurochemical changes that negatively impact feeding and mood regulation.
Nutritional Neuroscience, 2000
The present study examines effects of diet restriction (DR) on behavior and on the opioid peptides enkephalin (Enk) and dynorphin (Dyn). Female rats were assigned to ad libitum food intake (AL), DR 60% (DR60) or 40% (DR40) of AL. After 4 weeks, DR reduced fearful behavior in the elevated plus maze. DR rats displayed good retention of passive avoidance at 24 h, but DR40 rats had reduced retention, at 5 and 11 days post training. Changes in Enk-and Dyn-like immunoreactivity (LI) in the hippocampal mossy fibers (MF), hypothalamus, septum, central nucleus of amygdala (CeAm) and thalamus depended on the severity of DR. In DR60, Enk-LI and Dyn-LI were not changed except for reduction in CeAm. In DR40, Dyn-LI increased significantly above AL levels in MF, CeAm and hypothalamus, whereas Enk-LI increased significanUy above AL levels in the CA3 subregion of the MF system and in thalamus. Serum glucose was tighUy correlated with Enk-LI reaching highest values in the MF (r=-0.82). Increased opioid-LI in CeAm and MF was associated with reduced fearfulness in the elevated plus maze. Thus, hippocampal and amygdala opioid subsystems are uniquely sensitive to DR and may be relevant to psychophysiological problems in human starvation including anorexia.
Neurochemical and Pharmacological Studies in rat model of diet restriction-induced Anorexia
Journal of Cerebral Blood Flow & Metabolism
Anorexia nervosa (AN) patients exhibit extreme dieting, body weight loss and hyperactivity. The 5-hydroxytryptamine (5-HT; serotonin) system involved in the regulation of appetite and mood is the major neurotransmitter system of interest in research on AN. Pharmacological studies show that manipulations that tend to increase brain serotonin functions are anorexiogenic. The hypothesis of suppression of appetite through excessive release of 5-HT to receptors is not supported by data on subjects with clinical symptoms of AN as cerebrospinal (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT, are reduced in AN patients and returned to normal in recovered patients. Loss of appetite in AN may simply follow self imposed dieting and diet restriction (DR). The hypothalamus is believed to be the site of the brain transducing satiety signals of serotonin. Studies on animal models show that excessive DR decreases 5-HT metabolism and synthesis in the brain and hypoth...
Serotonergic modulation of conditioned fear
Scientifica, 2012
Conditioned fear plays a key role in anxiety disorders as well as depression and other neuropsychiatric conditions. Understanding how neuromodulators drive the associated learning and memory processes, including memory consolidation, retrieval/expression, and extinction (recall), is essential in the understanding of (individual differences in vulnerability to) these disorders and their treatment. The human and rodent studies I review here together reveal, amongst others, that acute selective serotonin reuptake inhibitor (SSRI) treatment facilitates fear conditioning, reduces contextual fear, and increases cued fear, chronic SSRI treatment reduces both contextual and cued fear, 5-HT1A receptors inhibit the acquisition and expression of contextual fear, 5-HT2A receptors facilitates the consolidation of cued and contextual fear, inactivation of 5-HT2C receptors facilitate the retrieval of cued fear memory, the 5-HT3 receptor mediates contextual fear, genetically induced increases in se...
Extinction theory & anorexia nervosa: Deepening therapeutic mechanisms
By virtue of adopting the core symptomatic fear (i.e., a fear of weight gain) as a primary treatment target, the treatment of AN centrally involves exposure-driven processes. However, exposure trials targeting the fear of weight gain in AN have been sparse, yielding mixed results to date. In translating extinction theory to the treatment of AN, it is likely that the absence of a clear distinction between what constitutes the core feared cue and the core feared outcome has stymied the application of exposure treatments in AN. This review considers several configurations of the core fear association in AN, noting distinct therapeutic strategies which may allow for more precise efforts in violating fear-based expectancies. Specific guidance is offered in the clinical decision making process as to which strategies might best promote inhibitory learning, and a clinical case is discussed, in which treatment was adjusted to specifically violate the core underlying fear association.
Fasting enhances extinction retention and prevents the return of fear in humans Shi
Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship with the fear response in spontaneous recovery test. However, overnight fasting did not affect cortisol levels. These findings indicate that fasting enhances extinction retention and prevents the return of fear, without influencing fear memory formation. We propose that this novel procedure may open new avenues for promoting extinction-based therapies for fear-related disorders.
Brain Sciences
Adolescence is a developmental phase characterized by emotional turmoil and coincides with the emergence of affective disorders. Inherited serotonin transporter (5-HTT) downregulation in humans increases sensitivity to these disorders. To reveal whether and how 5-HTT gene variance affects fear-driven behavior in adolescence, we tested wildtype and serotonin transporter knockout (5-HTT−/−) rats of preadolescent, adolescent, and adult age for cued fear extinction and extinction recall. To analyze neural circuit function, we quantified inhibitory synaptic contacts and, through RT-PCR, the expression of c-Fos, brain-derived neurotrophic factor (BDNF), and NDMA receptor subunits, in the medial prefrontal cortex (mPFC) and amygdala. Remarkably, the impaired recall of conditioned fear that characterizes preadolescent and adult 5-HTT−/− rats was transiently normalized during adolescence. This did not relate to altered inhibitory neurotransmission, since mPFC inhibitory immunoreactivity was ...
Fasting enhances extinction retention and prevents the return of fear in humans
Translational psychiatry, 2018
Fear is prone to return following extinction that is the basis of exposure therapy for fear-related disorders. Manipulations that enhance the extinction process can be beneficial for treatment. Animal studies have shown that fasting or caloric restriction can enhance extinction and inhibit the return of fear. The present study examined the effects of fasting on fear acquisition, extinction, and the return of fear in humans. One hundred and twenty-five male participants were randomized into a fasting group and food group and exposed to a Pavlovian fear conditioning paradigm. Changes in plasma cortisol and ghrelin levels were examined using enzyme-linked immunosorbent assays. One-night fasting had no effect on fear acquisition but enhanced fear extinction retention and prevented the return of fear, and this effect persisted for at least 6 months. This procedure was also effective for remote fear memory. Plasma ghrelin levels were elevated after fasting and had a negative relationship ...