Low-frequency stimulation of the hippocampus following fear extinction impairs both restoration of rapid eye movement sleep and retrieval of extinction memory

Post-learning rapid eye movement (REM) sleep deprivation has often been shown to impair hippocampal functioning, which results in deficit in retrieval of some types of memory. However, it remains to be determined whether post-learning alteration of hippocampal functioning affects, in turn, REM sleep. Recent studies have shown that both post-extinction REM sleep deprivation and post-extinction application of hippocampal low-frequency stimulation (LFS) impair memory of fear extinction, indicating possible bidirectional interactions between hippocampal functioning and REM sleep. To analyze the potential effect of post-extinction alteration of hippocampal functioning on REM sleep, rats were implanted with stimulating electrodes in the dorsal hippocampus for post-extinction LFS. Sleep was recorded before (two sessions, 1 day apart) and after conditioning (five tone and eyelid-shock pairings), and following extinction training (25 tone-alone presentations) for 6 h per session. Fear conditioning reduced time spent in REM sleep, which was restored with fear extinction. Hippocampal LFS, applied immediately following extinction training, abolished the restorative effect of fear extinction on REM sleep and impaired extinction retrieval. These data extend previous findings and suggest bidirectional interactions between hippocampal functioning and REM sleep for successful extinction retrieval.     

Bidirectional selection for susceptibility to ethanol withdrawal seizures inMus musculus

Using within-family selection from a genetically heterogeneous population of HS/Ibg mice, lines and replicates have been selected for high (withdrawal seizure prone; WSP) and low (withdrawal seizure resistant; WSR) susceptibility to convulsions after withdrawal from chronic exposure to ethanol. Two nonselected control lines (withdrawal-seizure control; WSC) have also been maintained. The response was bidirectional in both replicates across 11 selected generations, WSP and WSR lines differing approximately 10-fold in seizure severity after an identical regimen of chronic exposure to ethanol. Realized heritability was found to be approximately 0.28. The phenotype appears to be polygenic in nature. The relatively low amount of inbreeding in these lines and the large response to selection should make them useful for examining the physiological basis of physical dependence on ethanol.     

条件性恐惧记忆再巩固的神经分子机制研究

<正>创伤后应激障碍(post-traumatic stress disorder,PTSD)是经历强烈创伤性事件的个体再次暴露在相似创伤情境时出现以恐惧记忆重复体验为核心症状的反应性精神障碍~([1])。正常的恐惧记忆和恐惧反应是人和动物重要的生存活动,可以帮助机体启动防御机制。然而对于PTSD患者来说,这种恐惧记忆引起的恐惧反应被某些神经生理机制扩大并长期巩固,对患者造成了严重的身心伤害。近年来随着恐     

Context fear learning and renewal of extinguished fear are dissociated in juvenile female rats

Extinction is the decrease in emotion to a cue that was previously associated with an emotionally significant event. It involves repeated presentation of the cue without any consequences. In adult animals, extinguished fear to a cue can return if the cue is presented in a different environment/context to where extinction occurred, referred to as renewal. We have previously reported that developing female, but not male, rats show renewal. This study investigates whether the ability of developing female rats to show renewal is related to their ability in fear conditioning to the context. Additionally, facilitation of context conditioning by weaning previously shown in male rats was tested in developing female rats. In experiment 1, postnatal day 25 (P25) and P18 female rats showed renewal. P25 rats show more fear overall, suggesting a weaker extinction recall in this age. Experiment 2 tested context- and cue-elicited fear either immediately or 24 hr following conditioning. At the immediate test, P18 rats showed less context-fear compared with P25 rats. All rats showed low levels of context-fear at the 24 hr test. There were no age differences in cued fear. Weaning at P21 did not affect context or cue memory in P25 female rats. These findings suggest that the ability to form contextual fear memory is unrelated to the expression of renewal in juvenile female rats.     

Sources of energy for the brain and physical dependence on ethanol.

This paper describes a proposed biochemical mechanism to account for physical dependence on ethanol. Long-term exposure to a continuous and plentiful supply of ethanol-derived hydrogens in NADH and ethanol-derived acetyl-CoA (AcCoA) may lead to a decreased rate of production of endogenous hydrogens in NADH and endogenous AcCoA in compensation. It is proposed that physical dependence on ethanol occurs when ketolytic- and glycolytic-based NADH and AcCoA synthetic rates fall below the rate of utilization by the brain; the brain then "depends" on alcohol-derived NADH and AcCoA for normal function.     

Connection between withdrawal analgesia and development of heart disturbances in rats with an ethanol withdrawal syndrome

Laboratory of Toxicology, All-Union Research Center for Medico-Biological Problems in Drug Addiction, Ministry of Health of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. V. Val'dman.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 108, No. 9, pp. 274–276, September, 1989.     

Seven generations of genetic selection for ethanol dependence in mice

An animal model of alcohol dependence is being produced by selecting mice for differences in severity of ethanol withdrawal seizures. Replicate lines of high-dependence (HA), low-dependence (LA), and control (CA) mice are being developed by within-family selection. After seven generations both (replicate) HA and LA lines have separated significantly. Some of the difference between the replicate pairs of HA and LA in the early generations was due to differences in ethanol consumption. This difference in consumption may be attributable to a difference in metabolic rate or activity level rather than to a difference in ethanol preference. Females are more susceptible to seizures than males; this appears to be due partly to their higher consumption of ethanol during treatment.This research was supported in part by Grant AA-03527 from the National Institute of Alcohol Abuse and Alcoholism to the University of Colorado Alcohol Research Center.     

The development of fear learning and generalization in 8-13 year-olds

The current study examined developmental changes in fear learning and generalization in 40 healthy 8–13 year‐olds using an aversive conditioning paradigm adapted from Lau et al. [Lau et al. [2008] Journal of the American Academy of Child and Adolescent Psychiatry 47:94–102]. In this task, the conditioned stimuli (CS+/CS?) are two neutral female faces, and the unconditioned stimulus is a fearful, screaming face. The second phase of the study also included a generalization stimulus (GS): a 50% blend of the CS± faces. The eye‐blink startle reflex was utilized to measure defensive responding. Patterns of fear learning and generalization were qualified by child age. Older children demonstrated greater fear learning (i.e., larger startle during CS+ than CS?) than younger children. In addition, older children exhibited the typical pattern of generalization observed in adults, whereas younger children did not. Finally, fear learning also related to contingency awareness; only children who correctly identified the CS+ demonstrated fear‐potentiated startle to the CS+. Clinical implications and future directions are discussed. © 2011 Wiley Periodicals,Inc. Dev Psychobiol 54: 675–684, 2012.     

NMDA receptors and the ontogeny of post-shock and retention freezing during contextual fear conditioning

The ontogeny and NMDA-receptor (NMDAR) mechanisms of context conditioning were examined during standard contextual fear conditioning (sCFC) – involving context and context-shock learning in the same trial – as a comparison with our previous reports on the Context Preexposure Facilitation Effect (CPFE), which separates these two types of learning by 24 hr. In Experiment 1, systemic administration of the NMDAR antagonist, MK-801, prior to conditioning disrupted retention but not post-shock freezing during sCFC in PD31 rats. Experiment 2 replicated and extended this effect to PD17 versus PD31 rats. Consistent with Experiment 1, pre-training MK-801 spared post-shock freezing but impaired retention freezing in PD31 rats. In contrast, pre-training MK-801 disrupted post-shock freezing in PD17 rats, which showed no retention freezing regardless of drug. These results reveal developmental differences in the role of NMDAR activity in the acquisition versus retention of a context-shock association during sCFC in pre-weanling and adolescent rats.     

Nicotine and extinction of fear conditioning

Despite known health risks, nicotine use remains high, especially in populations diagnosed with mental illnesses, including anxiety disorders and Post-Traumatic Stress Disorder (PTSD). Smoking in these populations may relate to the effects of nicotine on emotional memories. The current study examined the effects of nicotine administration on the extinction of conditioned fear memories. C57BL/6J mice were trained with two white noise conditioned stimulus (CS; 30 s, 85 dB)–foot shock (2 s, 0.57 mA) pairings. Extinction sessions consisted of six presentations of the CS (60 s) across multiple days. Mice were either tested in an AAA design, in which all stages occurred in the same context, or in an ABA design to identify if context changes alter extinction. Saline or nicotine was administered 5 min before training and/or extinction. In the AAA design, nicotine administration before training did not alter extinction. Nicotine administered prior to extinction sessions enhanced extinction and nicotine administered before training and extinction decreased extinction. In the ABA design, nicotine administered before extinction enhanced extinction and blocked context renewal of conditioned fear, while nicotine administered during training and extinction did not alter extinction but enhanced the context renewal of conditioned fear. Nicotine has a differential effect on extinction of fear conditioning depending on when it is administered. Administration during extinction enhances extinction whereas administration during training and extinction may strengthen contextual fear memories and interfere with extinction.     

Developmental aspects of fear: Comparing the acquisition and generalization of conditioned fear in children and adults

Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58: 471–481, 2016.     

The indirect amygdala-dorsal striatum pathway mediates conditioned freezing: insights on emotional memory networks

The dorsal striatum (DS) is involved in various forms of learning and memory such as procedural learning, habit learning, reward-association and emotional learning. We have previously reported that bilateral DS lesions disrupt tone fear conditioning (TFC), but not contextual fear conditioning (CFC) [Ferreira TL, Moreira KM, Ikeda DC, Bueno OFA, Oliveira MGM (2003) Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning. Brain Res 987:17-24]. To further elucidate the participation of DS in emotional learning, in the present study, we investigated the effects of bilateral pretest (postraining) electrolytic DS lesions on TFC. Given the well-acknowledged role of the amygdala in emotional learning, we also examined a possible cooperation between DS and the amygdala in TFC, by using asymmetrical electrolytic lesions, consisting of a unilateral lesion of the central amygdaloid nucleus (CeA) combined to a contralateral DS lesion. The results show that pre-test bilateral DS lesions disrupt TFC responses, suggesting that DS plays a role in the expression of TFC. More importantly, rats with asymmetrical pre-training lesions were impaired in TFC, but not in CFC tasks. This result was confirmed with muscimol asymmetrical microinjections in DS and CeA, which reversibly inactivate these structures. On the other hand, similar pretest lesions as well as unilateral electrolytic lesions of CeA and DS in the same hemisphere did not affect TFC. Possible anatomical substrates underlying the observed effects are proposed. Overall, the present results underscore that other routes, aside from the well-established CeA projections to the periaqueductal gray, may contribute to the acquisition/consolidation of the freezing response associated to a TFC task. It is suggested that CeA may presumably influence DS processing via a synaptic relay on dopaminergic neurons of the substantia nigra compacta and retrorubral nucleus. The present observations are also in line with other studies showing that TFC and CFC responses are mediated by different anatomical networks.     

Effects of ethanol consumption and withdrawal on B cell subpopulations in murine bone marrow.

We designed studies to examine the effects of ethanol consumption and withdrawal on the numbers of pre-B and B cells in murine bone marrow. Flow cytometric analysis of B220 and surface IgM expression on bone marrow cells revealed that consumption of ethanol by mice for 7 days led to a significant reduction in pre-B cells. The number of mature B cells in the bone marrow of these animals, however, did not differ from that of control mice. In contrast, examination of bone marrow obtained from mice at various times after withdrawal from ethanol showed significantly fewer numbers of mature B cells and an even greater loss of pre-B cells. This effect was seen for relatively long periods after withdrawal. These study findings are interpreted to suggest that ethanol consumption results in changes in the pre-B cell population in murine bone marrow. It also appears that withdrawal from ethanol results in more profound changes in the mature B cell population of the bone marrow than those that occur during ethanol consumption.     

大鼠场景性恐惧记忆再激活过程中海马HDAC2的表达变化

目的:探讨组蛋白去乙酰化酶2(histone deacetylase 2,HDAC2)在场景性恐惧记忆再激活过程中的表达变化。方法:对大鼠进行不可逃避的电击刺激与中性刺激(训练环境)联结匹配训练,建立大鼠场景性恐惧条件化模型,之后采用免疫组织化学、Western Blot和RT-PCR方法检测实验组(恐惧记忆唤起后30 min、2 h、6 h、24 h组和不进行恐惧记忆唤起的no-recall组)和对照组(与实验组相同的处理方式但没有足底电击的刺激)大鼠海马中HDAC2的表达变化。结果:免疫组织化学、Western Blot和RT-PCR方法检测结果均显示场景性恐惧记忆唤起后30 min与24 h,HDAC2在大鼠海马中的表达水平明显高于对照组,差异具有统计学意义。其它时间点及no-recall组HDAC2的表达与对照组相比,没有统计学意义。结论:场景性恐惧记忆唤起后30 min与24 h,HDAC2在大鼠海马中表达水平显著升高,此变化可能与恐惧记忆产生的相关行为(恐惧记忆的消退行为、焦虑行为等)有一定的联系。     

Extended fear conditioning reveals a role for both N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in the amygdala in the acquisition of conditioned fear

Pavlovian conditioning is a useful tool for elucidating the neural mechanisms involved with learning and memory, especially in regard to the stimuli associated with aversive events. The amygdala has been repeatedly implicated as playing a significant role in the acquisition and expression of fear. If the amygdala is critical for the acquisition of fear, then it should contribute to this processes regardless of the parameters used to induce or evaluate conditioned fear. A series of experiments using reversible inactivation techniques evaluated the role of the amygdala in the acquisition of conditioned fear when training was conducted over several days in rats. Fear-potentiated startle was used to evaluate the acquisition of conditioned fear. Pretraining infusions of N-methyl-d-aspartic acid (NMDA) or non-NMDA receptor antagonists alone into the amygdala interfered with the acquisition of fear early in training, but not later. Pretraining infusions of a cocktail consisting of both an NMDA and non-NMDA antagonist interfered with the acquisition of conditioned fear across all days of training. Taken together these results suggest the amygdala may potentially be critical for the acquisition of conditioned fear regardless of the parameters utilized.     

Resting heart rate variability is associated with inhibition of conditioned fear

Startle blink as well as skin conductance responses (SCR) are widely used indices of learning processes associated with fear conditioning and extinction. During safety learning, the amygdala is under top‐down inhibitory control by the prefrontal cortex (PFC). The capacity of the PFC to exert inhibitory control over subcortical brain structures may be indexed by resting state vagally mediated heart rate variability (HRV). The present study investigated the association of resting HRV with startle blink and SCR during conditioned fear inhibition and extinction. Participants first learned to discriminate a threat cue (A) signaling an aversive unconditioned stimulus from a safety signal (B), which were each presented together with a third stimulus X (AX+/BX?). Then, both the threat and safety signal were presented together (AB) to test whether the presence of the learned safety signal inhibits the fear response to the danger signal. Finally, AX was presented without reinforcement (AX?) to investigate fear extinction. Higher HRV was associated with pronounced fear inhibition and fear extinction. Resting HRV levels were associated with fear extinction as indexed by startle blink potentiation but not SCR, which presumably reflect more cognitive aspects of learning. Resting HRV may reflect the capacity of the prefrontal cortex to inhibit subcortical fear responses in the presence of safety or when former threat cues are presented in the absence of threat.     

Effect of lithium chloride on ethanol consumption by rats

Selective consumption of ethanol was produced in rats in the course of 2 months by giving a 5% solution of ethanol as the sole source of fluid. Lithium chloride, given by intraperitoneal injection in a dose of 35 mg/kg twice a day for 14 days, depressed the preference for ethanol by producing reversal of motivations, the mechanism of which is connected with changes in the activity of the hypothalamic centers of neuroendocrine regulation. The possible use of lithium salts in the treatment of chronic alcoholism is discussed.Laboratory of Pharmacology of the Nervous System and Laboratory of General Pharmacology, Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 6, pp. 693–696, June, 1977.