Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

Short- and long-term effects of cannabinoids on the extinction of contextual fear memory in rats

Facilitation of memory extinction by manipulation of the endocannabinoid (eCB) system has been recently studied in several paradigms. Our previous results pointed to facilitation of contextual fear memory extinction by a low dose of a cannabinoid agonist, with a suggestion of short-term effects. The aim of the present study was to further investigate the effects of cannabinoid drugs in the short- and long-term extinction of conditioned fear using an extended extinction protocol. Male Wistar rats were placed in a conditioning chamber and after 3 min received a footshock (1.5 mA, 1 s). On the next day, they received i.p. drug treatment (WIN55212-2 0.25 mg/kg, AM404 10 mg/kg, SR141716 A 1 mg/kg) and were re-exposed to the conditioning chamber for 30 min (extinction training). No-Extinction groups received the same drug treatment, but were exposed for 3 min to the conditioning chamber. A drug-free test of contextual memory (3 min) was performed 7 days later. The cannabinoid agonist WI55212-2 and the inhibitor of eCB metabolism/uptake AM404 facilitated short-term extinction. In addition, long-term effects induced by treatments with WIN55212 and AM404 were completely divergent to those of SR141716A treatment. The present results confirm and extend previous findings showing that the eCB system modulates short-term fear memory extinction with long-lasting consequences.     

Antagonism of lateral amygdala alpha1-adrenergic receptors facilitates fear conditioning and long-term potentiation

Norepinephrine receptors have been studied in emotion, memory, and attention. However, the role of alpha1-adrenergic receptors in fear conditioning, a major model of emotional learning, is poorly understood. We examined the effect of terazosin, an alpha1-adrenergic receptor antagonist, on cued fear conditioning. Systemic or intra-lateral amygdala terazosin delivered before conditioning enhanced short- and long-term memory. Terazosin delivered after conditioning did not affect consolidation. In vitro, terazosin impaired lateral amygdala inhibitory postsynaptic currents leading to facilitation of excitatory postsynaptic currents and long-term potentiation. Since alpha1 blockers are prescribed for hypertension and post-traumatic stress disorder, these results may have important clinical implications.Although norepinephrine (NE) has been widely studied as an important modulator of memory and emotion, comparatively little is known about the role of NE in amygdala-dependent Pavlovian fear conditioning, a major model for understanding the neural basis of fear learning and memory. In fear conditioning, an emotionally neutral conditioned stimulus (CS; i.e., tone) is temporally paired with an aversive unconditioned stimulus (US; i.e., footshock). After very few pairings, a lasting, robust CS–US association is acquired, and the CS elicits stereotypical defensive responses, including behavioral freezing (Blanchard and Blanchard 1969; Bolles and Fanselow 1980).The lateral nucleus of the amygdala (LA) is a key structure underlying fear conditioning (LeDoux 2000). Convergence of CS and US information in LA is believed to play an important role in initiating synaptic plasticity. Long-term potentiation (LTP)-like changes in LA CS processing are critical for fear memory storage (LeDoux 2000; Blair et al. 2001; Maren 2001; Walker and Davis 2002). LA receives auditory CS inputs from the thalamus and cortex and connects directly and indirectly with the central nucleus of the amygdala to control expression of Pavlovian fear responses.Of the noradrenergic receptor subtypes, alpha1 receptors have received the least attention in fear conditioning. LA receives NE-containing inputs from the locus coeruleus that fire tonically and phasically in response to aversive stimuli like footshock (Pitkänen 2000; Tanaka et al. 2000; Aston-Jones and Cohen 2005). Alpha1-adrenergic receptors are expressed in LA, most likely on both excitatory and inhibitory neurons (Jones et al. 1985; Domyancic and Morilak 1997). Alpha1 receptor activation stimulates GABA-mediated miniature inhibitory postsynaptic currents in LA (Braga et al. 2004), suggesting that alpha1 receptors contribute to inhibition in fear conditioning pathways. Several elegant experiments recently demonstrated that LA inhibition gates synaptic plasticity necessary for fear conditioning, and this inhibitory gate can be influenced by neuromodulators including NE (Stutzmann and LeDoux 1999; Shumyatsky et al. 2002; Bissière et al. 2003; Shaban et al. 2006; Shin et al. 2006; Tully et al. 2007). However, the role of alpha1 receptor activity in gating amygdala LTP and fear learning has never been examined.We hypothesized that alpha1 blockers would facilitate fear learning, possibly by impairing LA inhibition and facilitating LA LTP. To test this hypothesis, we injected rats with terazosin, a selective alpha1-adrenergic receptor antagonist, systemically or directly into LA before or after fear conditioning. We examined in vitro the effect of terazosin on LA pyramidal cell inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs) in response to fiber stimulation of the thalamic CS input pathway to LA, as well as the effect of terazosin on LA LTP in this same pathway. We found that intra-LA terazosin facilitated fear conditioning when injected before but not after training. We also found that terazosin impaired IPSCs in LA pyramidal cells, leading to facilitated EPSCs and LTP.Behavioral experiments were conducted on adult, male Sprague–Dawley rats (Hilltop Laboratory Animals) weighing approximately 300 g upon arrival. Rats were individually housed, maintained on a 12/12 h light/dark schedule, and allowed free access to food and water. Testing was conducted during the light phase. All procedures and experiments were approved by NYU''s Animal Care and Use Committee.For systemic injections, terazosin (20 mg/kg; Sigma) was dissolved in saline and injected intraperitoneally (i.p.) 30 min prior to conditioning in 1 mL/kg volume. For bilateral infusions, terazosin (125 ng/0.25 µL) was dissolved in aCSF and infused into the LA at 0.1 µL/min 30 min prior to or immediately after fear conditioning. Bilateral guide cannulae (22 gauge; Plastics One) aimed at LA (−3.3 mm anterior, 5.2 mm lateral, −7 mm dorsal to bregma) were surgically implanted as previously described (Sotres-Bayon et al. 2009). Rats were given at least 7 d to recover from surgery before testing. For infusions, dummy cannulae were removed, and infusion cannulae (28 gauge, +1 mm beyond guides) were inserted into guides. Infusion cannulae were connected to a 1.0 μL Hamilton syringe via polyethylene tubing. Infusion rate was controlled by a pump (PHD22/2000; Harvard Apparatus), and infusion cannulae were left in place for an additional 60 sec to allow diffusion of the solution away from the cannula tip, then dummy cannulae were replaced. Upon completion of the experiment, rats were euthanized, brains removed, and cannulae placements verified histologically as previously described (Sotres-Bayon et al. 2009).Two contexts (A and B) were used for all testing as previously described (Schiller et al. 2008). The grid floors in Context B were covered with black Plexiglas inserts to reduce generalization. No odors were used and chambers were cleaned between sessions. CSs were 30 sec, 5 kHz, 80 dB tones, and USs were 1 sec, 0.8 mA scrambled electric footshocks. Experiments consisted of two phases separated by 48 h: (1) fear conditioning in Context A and (2) long-term memory (LTM) test in Context B. On Day 1, rats were placed in Context A, allowed 5 min to acclimate, and then received three CS–US pairings separated by variable 5 min ITIs. On Day 3, rats were placed in Context B and allowed 5 min to acclimate before receiving one CS-alone presentation.The index of fear in behavioral experiments was “freezing,” the absence of all non-respiratory movement (Blanchard and Blanchard 1971; Fanselow 1980). Following testing, freezing was manually scored from DVDs by a scorer blind to group specification. Graphs represent group means ± SEM. Statistical analysis was conducted with GraphPad Prism.Whole-cell electrophysiological recordings were obtained from LA pyramidal cells using in vitro coronal slices from rats aged P21–P30 d as described in Cunha et al. (2010). Terazosin was bath-applied for 10 min to achieve stable responses before testing. The cells were voltage-clamped using an Axopatch 200B amplifier at −35 mV for recording EPSCs and IPSCs. Synaptic responses were evoked with sharpened tungsten bipolar stimulating electrodes. Internal capsule fibers containing thalamic afferents were stimulated for paired-pulse facilitation (PPF) (ISI = 50 msec; 0.1 Hz) using a photoelectric stimulus isolation unit with a constant current output. Cells were rejected if access resistance (8–26 MΩ) changed more than 15%. Signals were filtered at 2 kHz and digitized (Digidata 1440 A; Axon Instruments), and peak amplitude, 10%–90% rise time, and IPSC decay time constants were analyzed offline using pCLAMP10.2 software (Axon Instruments).Brain slices for LTP experiments were prepared from rats aged 3–5 wk as in Johnson et al. (2008) and maintained on an interface chamber at 31°C. Glass recording electrodes (filled with aCSF, 5 MΩ resistance) were guided to LA neurons. Bipolar stainless steel stimulating electrodes (75 kΩ) were positioned medial to LA in internal capsule fibers. Orthodromic synaptic potentials were evoked via an isolated current generator (Digitimer; 100 μsec pulses of 0.3–0.7 mA). Evoked field potentials were recorded with an Axoclamp 2B amplifier and Axon WCP software (Axon Instruments). Data were analyzed offline using WCP PeakFit (Axon Instruments). LTP was measured as a change in evoked field potential amplitude.Baseline responses were monitored at 0.05 Hz for 30 min with a stimulus intensity of 40%–50% of maximum fEPSP before LTP induction. Terazosin (10 µM) was superfused for 15 min, and then LTP was elicited by three tetanus trains (100 Hz × 1 sec, 3 min ITI) with the same intensity and pulse duration as the baseline stimuli. In one experiment, picrotoxin (PTX; 75 µM) was present in the perfusion solution to block fast GABAergic signaling.     

Role of the somatostatin system in contextual fear memory and hippocampal synaptic plasticity

Somatostatin has been implicated in various cognitive and emotional functions, but its precise role is still poorly understood. Here, we have made use of mice with somatostatin deficiency, based upon genetic invalidation or pharmacologically induced depletion, and Pavlovian fear conditioning in order to address the contribution of the somatostatin system to associative fear memory. The results demonstrate an impairment of foreground and background contextual but not tone fear conditioning in mice with targeted ablation of the somatostatin gene. These deficits were associated with a decrease in long-term potentiation in the CA1 area of the hippocampus. Both the behavioral and the electrophysiological phenotypes were mimicked in wild-type mice through application of the somatostatin-depleting substance cysteamine prior to fear training, whereas no further deficits were observed upon application in the somatostatin null mutants. These results suggest that the somatostatin system plays a critical role in the acquisition of contextual fear memory, but not tone fear learning, and further highlights the role of hippocampal synaptic plasticity for information processing concerning contextual information.     

Neonatal tactile stimulation enhances spatial working memory, prefrontal long-term potentiation, and D1 receptor activation in adult rats

Environmental stimuli during neonatal periods play an important role in the development of cognitive function. In this study, we examined the long-term effects of neonatal tactile stimulation (TS) on spatial working memory (SWM) and related mechanisms. We also investigated whether TS-induced effects could be counteracted by repeated short periods of maternal separation (MS). Wistar rat pups submitted to TS were handled and marked transiently per day during postnatal days 2–9 or 10–17. TS/MS pups were stimulated in the same way as TS pups and then individually separated from their mother for 1 h/day. Their nontactile stimulated (NTS) siblings served as controls. In adulthood, TS and TS/MS rats showed better performance in two versions of the delayed alternation task and superior in vivo long-term potentiation of the hippocampo–prefrontal cortical pathway when compared with controls. Furthermore, there were more doses of A77636 (a selective dopamine D1 agonist) to significantly improve SWM performance in TS and TS/MS rats than in NTS rats, suggesting that activation of prefrontal D1 receptors in TS and TS/MS rats is more optimal for SWM function than in NTS rats. MS did not counteract TS-induced effects because no significant difference was found between TS/MS and TS animals. These data indicate that in early life, external tactile stimulation leads to long-term facilitative effects in SWM-related neural function.     

Biphasic ERK1/2 activation in both the hippocampus and amygdala may reveal a system consolidation of contextual fear memory

There is accumulating evidences to suggest that memory consolidation in some conditions involves two waves of neuronal plastic change. Using two fear conditioning procedures in male C57BL/6J mice, we have recently shown that consolidation of the foreground contextual fear memory required two waves of ERK1/2 activation in hippocampal CA1, while consolidation of cue conditioning was only associated with the early phase of activation. The present experiment further showed that this bi-phasic pattern of ERK1/2 activation was not restricted to hippocampal CA1, but could also be observed in other fear memory-related brain areas. The unpaired conditioning procedure (context in foreground) induced two waves of ERK1/2 activation in hippocampal CA1 and CA3, as well as in the LA and BLA nuclei of the amygdala. In contrast, the paired conditioning procedure (context in background) led to a transient early phase only in hippocampal CA1 and LA. In addition, ERK1/2 phosphorylation in the hippocampus was found to correlate with that in the amygdala nuclei specifically after the unpaired procedure. Taken together, our data suggest that the observed biphasic pattern of neuronal plastic events may reflect the interplay between hippocampal and amygdala activity-dependent plasticity critical for the system consolidation of contextual fear memory.     

Role of muscarinic M1 receptors in inhibitory avoidance and contextual fear conditioning

The objective of the present study was to observe the effects of pre-training or post-training administration of dicyclomine, a M1 muscarinic antagonist, on inhibitory avoidance (IA) and contextual fear conditioning (CFC) and to investigate if the effects observed with the pre-training administration of dicyclomine are state-dependent. For each behavioral procedure (IA and CFC) groups of Wistar male rats were treated with saline or dicyclomine either 30 min before training (pre-training), immediately after training or 30 min before training/30 min before test (pre-training/pre-test). The animals were tested 24 h after training. The acquisition of IA and CFC was impaired by pre-training administration of dicyclomine. The consolidation of both tasks was not affected by dicyclomine given immediately after training. Pre-training/pre-test administration of dicyclomine impaired both tasks, an effect similar to that observed in the group which only received pre-training administration. Pre-test treatment induced dissociation between both tasks, impairing CFC retrieval, without interfering with the animals avoidance response. These results show that the dicyclomine did not affect IA and CFC consolidation, suggesting specific involvement of M1 muscarinic receptor only in acquisition these tasks, and these effects was not state-dependent. However, it is possible that the retrieval of these tasks may be mediated, at least in part, by different neurochemical mechanisms and may be dissociated by dicyclomine.     

Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex

Phosphatidylinositol 3-kinase (PI3K) and its downstream targets, including Akt (also known as protein kinase B, PKB), mammalian target of rapamycin (mTOR), the 70-kDa ribosomal S6 kinase (p70S6k), and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), may play important roles in long-term synaptic plasticity and memory in many brain regions, such as the hippocampus and the amygdala. The present study investigated the role of the PI3K/Akt-mTOR signaling pathway in the medial prefrontal cortex (mPFC), also a crucial neural locus for the control of cognition and emotion. Western blot analysis of mPFC tissues showed an activation of phosphorylation of Akt at the Ser473 residues, mTOR, p70S6k, and 4E-BP1 in response to long-term potentiation (LTP)-inducing high-frequency stimulation (HFS). Infusion of PI3K inhibitors (wortmannin and LY294002) and an mTOR inhibitor (rapamycin) into the mPFC in vivo suppressed HFS-induced LTP as well as the phosphorylation of PI3K/Akt-mTOR signaling pathway. In parallel, these inhibitors interfered with the long-term retention of trace fear memory examined 3 d and 6 d after the trace fear conditioning training, whereas short-term trace fear memory and object recognition memory were kept intact. These results provide evidence of involvement of activation of the PI3K/Akt-mTOR signaling pathway in the mPFC for LTP and long-term retention of trace fear memory.     

Differential effects of cannabinoid receptor agonist on social discrimination and contextual fear in amygdala and hippocampus

We examined whether the cannabinoid receptor agonist WIN55,212-2 (WIN; 5 μg/side) microinjected into the hippocampus or the amygdala would differentially affect memory processes in a neutral vs. an aversive task. In the aversive contextual fear task, WIN into the basolateral amygdala impaired fear acquisition/consolidation, but not retrieval. In the ventral subiculum (vSub), WIN impaired fear retrieval. In the neutral social discrimination task, WIN into the vSub impaired both acquisition/consolidation and retrieval, whereas in the medial amygdala WIN impaired acquisition. The results suggest that cannabinoid signaling differentially affects memory in a task-, region-, and memory stage-dependent manner.     

Posttraining glucocorticoid receptor agonist enhances memory in appetitive and aversive Pavlovian discrete-cue conditioning paradigms

Glucocorticoid modulation of emotional memory has repeatedly been shown in aversive learning paradigms, but has received little attention in appetitive tasks. It has also been suggested that it may be selective for contextual cues. In order to investigate if glucocorticoids can modulate memory in discrete-cue conditioning of both appetitive and aversive tasks, two experiments were carried out. Male Lister-Hooded rats received pairings of an auditory cue and either food-reward (experiment 1) or footshock (experiment 2), followed immediately by posttraining injections of the glucocorticoid receptor agonist dexamethasone (0.3, 0.6, and 1.2 mg/kg) or vehicle. Dexamethasone (1.2 mg/kg) led to significantly enhanced learning. These results give support to the notion that glucocorticoids play a role in the modulation of both appetitive and aversive emotional memories and show that their role in learning goes beyond the construction of context representations. The modulation of appetitive and aversive discrete-cue learning may be subserved by a common mechanism.     

Complex effects of NMDA receptor antagonist APV in the basolateral amygdala on acquisition of two-way avoidance reaction and long-term fear memory

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about an involvement of this structure in more complex aversive learning, such as acquisition of an active avoidance reaction. In the present study, rats with a pretraining injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), into the basolateral amygdala (BLA) were found to be impaired in two-way active avoidance learning. During multitrial training in a shuttle box, the APV-injected rats were not different from the controls in sensitivity to shock or in acquisition of freezing to contextual cues. However, APV injection led to impaired retention of contextual fear when tested 48 h later, along with an attenuation of c-Fos expression in the amygdala. These results are consistent with the role of NMDA receptors of the BLA in long-term memory of fear, previously documented in Pavlovian conditioning paradigms. The APV-induced impairment in the active avoidance learning coincided with deficits in directionality of the escape reaction and in attention to conditioned stimuli. These data indicate that normal functioning of NMDA receptors in the basolateral amygdala is required during acquisition of adaptive instrumental responses in a shuttle box but is not necessary for acquisition of short-term contextual fear in this situation.     

Posttraining activation of CB1 cannabinoid receptors in the CA1 region of the dorsal hippocampus impairs object recognition long-term memory

Evidence indicates that brain endocannabinoids are involved in memory processing. However, the participation of CB1 and CB2 cannabinoid receptors in recognition memory has not been yet conclusively determined. Therefore, we evaluated the effect of the posttraining activation of hippocampal cannabinoid receptors on the consolidation of object recognition memory. Rats with infusion cannulae stereotaxically aimed to the CA1 region of the dorsal hippocampus were trained in an object recognition learning task involving exposure to two different stimulus objects. Memory retention was assessed at different times after training. In the test sessions, one of the objects presented during training was replaced by a novel one. When infused in the CA1 region immediately after training, the non-selective cannabinoid receptor agonist WIN-55,212-2 and the endocannabinoid membrane transporter inhibitor VDM-11 blocked long-term memory retention in a dose-dependent manner without affecting short-term memory, exploratory behavior, anxiety state or the functionality of the hippocampus. The amnesic effect of WIN-55,212-2 and VDM-11 was not due to state-dependency and was completely reversed by co-infusion of the CB1 receptor antagonist AM-251 and mimicked by the CB1 receptor agonist ACEA but not by the CB2 receptor agonists JWH-015 and palmitoylethanolamide. Our data indicate that activation of hippocampal CB1 receptors early after training hampers consolidation of object recognition memory.     

Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

Superoxide has been shown to be critically involved in several pathological manifestations of aging animals. In contrast, superoxide also can act as a signaling molecule to modulate signal transduction cascades required for hippocampal synaptic plasticity. Mitochondrial superoxide dismutase (SOD-2 or Mn-SOD) is a key antioxidant enzyme that scavenges superoxide. Thus, SOD-2 may not only prevent aging-related oxidative stress, but may also regulate redox signaling in young animals. We used transgenic mice overexpressing SOD-2 to study the role of mitochondrial superoxide in aging, synaptic plasticity, and memory-associated behavior. We found that overexpression of SOD-2 had no obvious effect on synaptic plasticity and memory formation in young mice, and could not rescue the age-related impairments in either synaptic plasticity or memory in old mice. However, SOD-2 overexpression did decrease mitochondrial superoxide in hippocampal neurons, and extended the lifespan of the mice. These findings increase our knowledge of the role of mitochondrial superoxide in physiological and pathological processes in the brain.     

Context preexposure prevents forgetting of a contextual fear memory: implication for regional changes in brain activation patterns associated with recent and remote memory tests

Contextual fear conditioning was maintained over a 15-day retention interval suggesting no forgetting of the conditioning experience. However, a more subtle generalization test revealed that, as the retention interval increased, rats showed enhanced generalized fear to an altered context. Preexposure to the training context prior to conditioning, however, prevented this enhanced generalized fear from developing. These results support the hypothesis that the memory representation of the context degrades as the memory ages and is responsible for enhanced generalization. The implications of these results for systems consolidation versus forgetting interpretations of regional changes in neural activation patterns that occur as memories age are discussed.     

CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice

Cannabinoid receptors type 1 (CB1) play a central role in both short-term and long-term extinction of auditory-cued fear memory. The molecular mechanisms underlying this function remain to be clarified. Several studies indicated extracellular signal-regulated kinases (ERKs), the phosphatidylinositol 3-kinase with its downstream effector AKT, and the phosphatase calcineurin as potential molecular substrates of extinction behavior. To test the involvement of these kinase and phosphatase activities in CB1-dependent extinction of conditioned fear behavior, conditioned CB1-deficient mice (CB1(-/-)) and wild-type littermates (CB1(+/+)) were sacrificed 30 min after recall of fear memory, and activation of ERKs, AKT, and calcineurin was examined by Western blot analysis in different brain regions. As compared with CB1(+/+), the nonreinforced tone presentation 24 h after auditory-cued fear conditioning led to lower levels of phosphorylated ERKs and/or calcineurin in the basolateral amygdala complex, ventromedial prefrontal cortex, dorsal hippocampus, and ventral hippocampus of CB1(-/-). In contrast, higher levels of phosphorylated p44 ERK and calcineurin were observed in the central nucleus of the amygdala of CB1(-/-). Phosphorylation of AKT was more pronounced in the basolateral amygdala complex and the dorsal hippocampus of CB1(-/-). We propose that the endogenous cannabinoid system modulates extinction of aversive memories, at least in part via regulation of the activity of kinases and phosphatases in a brain structure-dependent manner.     

Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: Evidence for a dual-process memory model

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1^−/− mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1^−/− mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.     

Age-related differences in working memory and force control under dual-task conditions

The aim of this study was to investigate the relationship between force control and cognitive performance under dual-task conditions in younger (18-22 years) and older adults (65-77 years). Cognitive (n-back test) and motor performance (force-tracking) was measured independently and simultaneously. Results indicated overall age-related differences for the n-back and the force-tracking task. Age-related differences increased during dual-task conditions. While younger adults exhibited no decrease in cognitive or motor performance during dual-task conditions, older adults showed a decrease in motor and cognitive performance. Additionally, when older adults made an error in the cognitive task they tended to show greater variability in the force-tracking task. These results suggest that cognitive motor deficits are responsible for older adults' performance decrements under dual-task conditions.     

Differential roles for hippocampal areas CA1 and CA3 in the contextual encoding and retrieval of extinguished fear

Recent studies demonstrate that context-specific memory retrieval after extinction requires the hippocampus. However, the contribution of hippocampal subfields to the context-dependent expression of extinction is not known. In the present experiments, we examined the roles of areas CA1 and CA3 of the dorsal hippocampus in the context specificity of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US), rats received extinction sessions in which the CS was presented without the US. In Experiment 1, pretraining neurotoxic lesions in either CA1 or CA3 eliminated the context dependence of extinguished fear. In Experiment 2, lesions of CA1 or CA3 were made after extinction training. In this case, only CA1 lesions impaired the context dependence of extinction. Collectively, these results reveal that both hippocampal areas CA1 and CA3 contribute to the acquisition of context-dependent extinction, but that only area CA1 is required for contextual memory retrieval.     

Intra-medial prefrontal administration of SCH-23390 attenuates ERK phosphorylation and long-term memory for trace fear conditioning in rats

The prefrontal cortex is known to be involved in the acquisition of trace conditioning, a higher-cognitive form of Pavlovian conditioning in which a conditioned stimulus and an unconditioned stimulus are separated by a time gap. We have recently reported that medial prefrontal (mPFC) extracellular-signal regulated kinase (Erk) phosphorylation is involved in the long-term memory storage of trace fear conditioning. Because of the important role dopamine D1 receptors play in prefrontal function, such as working memory, and due to evidence that dopamine D1 receptor activity can modulate plasticity, we investigated their role in prefrontal Erk phosphorylation following trace fear conditioning. We found that inhibition of dopamine D1 receptors through intra-mPFC infusion of SCH-23390 (1 microg/0.5 microL) 15 min prior to trace fear conditioning resulted in a decrease in training-related Erk phosphorylation. Additionally, pre-training intra-mPFC infusion of SCH-23390 also resulted in the impairment of long-term retention of CS-US association. These findings implicate mPFC dopamine D1 receptor activity in the storage of long-term memory for higher-cognitive associative tasks.