We investigated the neurobiological bases of variation in response to predator stress (PS). Sixteen days after treatment (PS or handling), rats were grouped according to anxiety in the elevated plus maze (EPM). Acoustic startle was also measured. We examined the structure of dendritic trees of basolateral amygdala (BLA) output neurons (stellate and pyramidal cells) and of dorsal hippocampal (DHC) dentate granule cells of less anxious (LA) and more (extremely) anxious (MA) stressed animals (PSLA and PSMA). Handled controls (HC) which were less anxious (HCLA) and spontaneously more anxious (HCMA) equivalently to predator stressed subgroups were also studied. Golgi analysis revealed BLA output neurons of HCMA rats exhibited longer, more branched dendrites with higher spine density than the other groups of rats, which did not differ. Finally, spine density of DHC granule cells was equally depressed in HCMA and PSMA rats relative to HCLA and PSLA rats. Total dendritic length of BLA pyramidal and stellate cells (positive predictor) and DHC spine density (negative predictor) together accounted for 96% of the variance of anxiety of handled rats. DHC spine density was a negative predictor of PSMA and PSLA anxiety, accounting for 70% of the variance. Data are discussed in the context of morphological differences as phenotypic markers of a genetic predisposition to anxiety in handled controls, and a possible genetic vulnerability to predator stress expressed as reduced spine density in the DHC. Significance of findings for animal models of anxiety and hyperarousal comorbidities of PTSD are discussed.
Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.
The mammalian target ofrapam ycin (mTOR) kinase is a critical regulator of mRNA translati on and is known to be involved in various long lasting forms of synapti c and behavioural plasticity. However, infonnation concerning the temporal pattern of mTOR activation and susceptibility to pharmacological intervention during both consolidation and reconsolidation ofl ong-term memory (L TM) remains scant. Male C57B L/6 mice were inj ected systemi call y wi th rapamycin at various time points fo llowing conditioning or retri eval in an auditory fear conditioning paradi gm, and compared to vehicle (and/or anisomycin) controls fo r subsequent memory recall. Systemic blockade of mTOR with rapamycin immediately or 12 hours after training or reactivation impaired both consolidati on and reconsolidati on of an auditory fear memory. Further behavioural analys is revealed that the enduring effects of rapamycin on reconsolidation were dependent upon reactivation of the memory trace. Rapamyci n, however, had no effect on short-term memory or the ability to retrieve an establ ished fear memory. Collectively, these data suggest that biphasic mTOR signalling is essential for both consolidation and reconsolidatio n-like activities that contribute to the fonnation, re-stabilization, and persistence of long tenn audi tory-fear memori es, while not infl uencing other aspects of the memory trace. These fi ndings also provide cogent evidence for a treatment model fo r acquired anxiety disorders such as posttraumatic stress d isorder (PTS D) and specific phobias, through phannacologic blockade of mTOR using systemic rapamycin fo llowing reacti vation.
Abstract-Allowing a resident hamster a single "priming" attack on a conspecific induces a transient aggressive arousal as indicated by a reduction in the latency and increase in the probability of attack on a second intruder presented within the next 30 min. We present two lines of evidence identifying the corticomedial amygdala as an important locus mediating this effect. (I) Attack priming significantly increases the number of neurons expressing immunocytochemically identified Fos protein in the corticomedial amygdala, but not elsewhere. Pursuit and biting of an inanimate object does not induce corticomedial amygdala c-fos expression of the same pattern or magnitude. The corticomedial amygdala contribution to the priming effect involves more than a non-specific arousal, since corticomedial amygdala c-fos expression does not correlate with locomotor activity, a standard indicator of such arousal. (2) Radiofrequency lesions of the corticomedial amygdala reduce aggression, the greatest reduction occurring with the more anterior lesions. Other behaviors, including a priming-like locomotor practice effect in a running wheel, are unaffected by corticomedial amygdala lesions. These findings suggest that attack priming is an aggression-specific effect resulting from a Fos-coupled change within neural circuitry of which the corticomedial amygdala is a part.From a theoretical point of view, these experiments suggest a new approach to the analysis of the mechanisms underlying aggressive behavior and the persistence of aggressive arousal. We present a sketch of a quantitative neurobehavioral model which relates attack probability to neural activation within the corticomedial amygdala. From a methodological viewpoint, these experiments extend the utility of mapping c-Ios expression as a technique for localizing endogenous, behavior-specific processes within the central nervous system. Copyright © 1996 !BRO. Published by Elsevier Science Ltd. appeared. To investigate the neural bases of such persisting aggressive arousal, we first developed a laboratory model of this phenomenon within the standard resident/intruder paradigm used in the study of rodent aggression. "Attack priming" a resident hamster by allowing it a single attack on a conspecific intruder introduced into its home cage reduces the latency and increases the probability of attack on a second, "probe" intruder. 47 ,52,53 This priming effect appears relatively specific in terms of both the responses it triggers and its effective stimuli.On the response side, we have found that other behaviors such as wheel running and eating (in female hamsters) and copulation (in male hamsters) are unaffected by priming 53 (Potegal, Hebert and Meyerhoff, unpublished observations). Experiment I of the present report examines the specificity of the stimulus by comparing the effects following attack priming to those following the detection, pursuit and biting of an inanimate object. Other experiments have eliminated a number of alternatives to the 869
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