Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering.

It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.

Alzheimer brain-derived amyloid ß-protein impairs synaptic remodeling and memory consolidation.

Aggregation of the amyloid ß-protein (Aß) is believed to play a central role in initiating the molecular cascade that culminates in Alzheimer-type dementia (AD), a disease which in its early stage is characterized by synaptic loss and impairment of episodic memory. Here we show that intracerebroventricular injection of Aß-containing water-soluble extracts of AD brain inhibits consolidation of the memory of avoidance learning in the rat and that this effect is highly dependent on the interval between learning and administration. When injected at 1 hour post training extracts from 2 different AD brains significantly impaired recall tested at 48 hours. Ultrastructural examination of hippocampi from animals perfused after 48 hours revealed that Aß-mediated impairment of avoidance memory was associated with lower density of synapses and altered synaptic structure in the dentate gyrus and CA1 fields. These behavioral and ultrastructural data suggest that human brain-derived Aß impairs formation of long-term memory by compromising the structural plasticity essential for consolidation and that Aß targets processes initiated very early in the consolidation pathway.

Inducible cAMP early repressor (ICER) and brain functions.

The inducible cAMP early repressor (ICER) is an endogenous repressor of cAMP-responsive element (CRE)-mediated gene transcription and belongs to the CRE-binding protein (CREB)/CRE modulator (CREM)/activating transcription factor 1 (ATF-1) gene family. ICER plays an important role in regulating the neuroendocrine system and the circadian rhythm. Other aspects of ICER function have recently attracted heightened attention. Being a natural inducible CREB antagonist, and more broadly, an inducible repressor of CRE-mediated gene transcription, ICER regulates long-lasting plastic changes that occur in the brain in response to incoming stimulation. This review will bring together data on ICER and its functions in the brain, with a special emphasis on recent findings highlighting the involvement of ICER in the regulation of long-term plasticity underlying learning and memory.

Inducible cAMP early repressor acts as a negative regulator for kindling epileptogenesis and long-term fear memory.

Long-lasting neuronal plasticity as well as long-term memory (LTM) requires de novo synthesis of proteins through dynamic regulation of gene expression. cAMP-responsive element (CRE)-mediated gene transcription occurs in an activity-dependent manner and plays a pivotal role in neuronal plasticity and LTM in a variety of species. To study the physiological role of inducible cAMP early repressor (ICER), a CRE-mediated gene transcription repressor, in neuronal plasticity and LTM, we generated two types of ICER mutant mice: ICER-overexpressing (OE) mice and ICER-specific knock-out (KO) mice. Both ICER-OE and ICER-KO mice show no apparent abnormalities in their development and reproduction. A comprehensive battery of behavioral tests revealed no robust changes in locomotor activity, sensory and motor functions, and emotional responses in the mutant mice. However, long-term conditioned fear memory was attenuated in ICER-OE mice and enhanced in ICER-KO mice without concurrent changes in short-term fear memory. Furthermore, ICER-OE mice exhibited retardation of kindling development, whereas ICER-KO mice exhibited acceleration of kindling. These results strongly suggest that ICER negatively regulates the neuronal processes required for long-term fear memory and neuronal plasticity underlying kindling epileptogenesis, possibly through suppression of CRE-mediated gene transcription.

Repeated withdrawal from ethanol spares contextual fear conditioning and spatial learning but impairs negative patterning and induces over-responding: evidence for effect on frontal cortical but not hippocampal function?

Repeated exposure of rats to withdrawal from chronic ethanol reduces hippocampal long-term potentiation and gives rise to epileptiform-like activity in hippocampus. We investigated whether such withdrawal experience also affects learning in tasks thought to be sensitive to hippocampal damage. Rats fed an ethanol-containing diet for 24 days with two intermediate 3-day withdrawal episodes, resulting in intakes of 13-14 g/kg ethanol per day, showed impaired negative patterning discrimination compared with controls and animals that had continuous 24-day ethanol treatment, but did not differ from these animals in the degree of contextual freezing 24 h after training or in spatial learning in the Barnes maze. Repeatedly withdrawn animals also showed increased numbers of responses in the period immediately before reinforcement became available in an operant task employing a fixed-interval schedule although overall temporal organization of responding was unimpaired. Thus, in our model of repeated withdrawal from ethanol, previously observed changes in hippocampal function did not manifest at the behavioural level in the tests employed. The deficit seen after repeated withdrawal in the negative patterning discrimination and over-responding in the fixed-interval paradigm might be related to the changes in the functioning of the cortex after withdrawal.

Previous experience of ethanol withdrawal increases withdrawal-induced c-fos expression in limbic areas, but not withdrawal-induced anxiety and prevents withdrawal-induced elevations in plasma corticosterone.

RATIONALE: Increased anxiety is a characteristic of the acute ethanol withdrawal syndrome. Repeated exposure of rats to withdrawal from chronic ethanol increases sensitivity to seizures. OBJECTIVES: We investigated whether repeated withdrawal experience increases withdrawal-induced anxiety and stress, and if it changes withdrawal-induced activation of related brain areas. METHODS: Rats were chronically treated with an ethanol-containing liquid diet either for 24 days continuously (single withdrawal, SWD) or interspersed with 2x3-day withdrawal periods (repeated withdrawal, RWD), or with a control diet. Eight hours after ethanol withdrawal, anxiety-like behaviour was tested in the elevated plus-maze, blood corticosterone levels were measured, and expression level of markers of neuronal activity and plasticity, c-fos and zif268, was assessed. RESULTS: Eight hours after ethanol withdrawal, SWD rats showed increased anxiety on the elevated plus-maze relative to control rats. Rats given previous withdrawal experiences did not show further increases in measures of anxiety. Corticosterone levels were elevated during withdrawal in SWD rats but not in RWD rats. RWD resulted in marked increases in c-fos expression in amygdala, hippocampus, nucleus accumbens and dorsolateral periaqueductal grey. In contrast, zif268 expression was not increased after RWD, and in central amygdala the marked increase in zif268 seen after SWD was absent after RWD. CONCLUSIONS: The data suggest increased ability of withdrawal to activate neuronal circuits but reduced plasticity after RWD. We suggest parallels between the consequences of repeated ethanol withdrawal and repeated exposure to stress, and discuss implications of withdrawal for brain plasticity.

Repeated ethanol exposure and withdrawal impairs human fear conditioning and depresses long-term potentiation in rat amygdala and hippocampus.

BACKGROUND: In rats, repeated episodes of alcohol consumption and withdrawal (RWD) impair fear conditioning to discrete cues. METHODS: Fear conditioning was measured in human binge drinkers as the increased startle response in the presence of a CS+ conditioned to aversive white noise. Secondly, the ability of tone CSs, paired with footshock, to induce c-fos expression, a marker of neuronal activity, in limbic structures subserving emotion was studied in rats. Additionally, consequences of RWD on subsequent induction of long term potentiation (LTP) in external capsule/lateral amygdala and Schaffer collateral/hippocampus CA1 pathways were studied in rat brain slices. RESULTS: Fear conditioning was impaired in young human binge drinkers. The ability of fear-conditioned CSs to increase c-fos expression in limbic brain areas was reduced following RWD, as was LTP induction. Rats conditioned prior to RWD, following RWD showed generalization of conditioned fear from the tone CS+ to a neutral control stimulus, and a novel tone. CONCLUSIONS: Binge-like drinking impairs fear conditioning, reduces LTP, and results in inappropriate generalization of learned fear responses. We propose a mechanism whereby RWD-induced synaptic plasticity reduces capacity for future learning, while allowing unconditioned stimuli access to neuronal pathways underlying conditioned fear.

Alcohol withdrawal and conditioning.

This review contains the proceedings from a symposium held at the RSA conference in 2003 on "Alcohol Withdrawal and Conditioning." The presentations covered a range of interactions between conditioning and alcohol withdrawal, in both animal behavior and the clinic. Dr. D.N. Stephens first described his studies exploring the consequences of alcohol dependence and repeated experience of withdrawal on the conditioning process. His data suggested that repeated withdrawal from moderate alcohol intake impairs amygdala-dependent mechanisms for learning about aversive events. Dr. H. Becker then detailed studies examining the consequences of repeated ethanol withdrawal experience on subsequent ethanol drinking behavior in mice, and conditions in which motivational properties of odor cues that are associated with different phases of ethanol withdrawal influence such relapse behavior. The data suggested that cues associated with acute withdrawal or "recovery" from withdrawal may serve as modulating factors in influencing subsequent ethanol drinking behavior, and that the timing of the cues determines their consequences. Dr. F. Weiss described recent findings from animal models of relapse that suggested the efficacy of alcohol-associated contextual stimuli in eliciting alcohol-seeking behavior resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans. The interactive effects of stress and ethanol-related environmental stimuli were found to be dependent on concurrent activation of endogenous opioid and corticotropin-releasing factor systems. Conditioning factors (i.e., exposure to drug-associated stimuli) and stress could therefore interact to augment vulnerability to relapse. Dr. C. Drummond then addressed the clinical aspects of conditioning during alcohol withdrawal and described studies showing exposure of alcoholics to alcohol-related cues elicited greater subjective and physiological responses than exposure to neutral cues. The former responsivity showed a relationship with a measure of motivation to drink alcohol. Finally, Dr. C. Cunningham provided a summary of the concepts involved in the presentations and discussed the conditioning processes that affect behavior during and after alcohol withdrawal.