Ethanol state-dependent memory: involvement of dorsal hippocampal muscarinic and nicotinic receptors

In the present study, the effects of bilateral injections of cholinergic agents into the hippocampal CA1 regions (intra-CA1) on ethanol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retention in adult male NMRI mice. Pre-training intraperitoneal injection (i.p.) of ethanol (0.25, 0.5 and 1 g/kg) dose dependently induced impairment of memory retention. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) induced state-dependent retrieval of the memory acquired under pre-training ethanol (1 g/kg, i.p.) influence. Pre-test intra-CA1 injection of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) improved pre-training ethanol (1 g/kg)-induced retrieval impairment. Moreover, pre-test administration of physostigmine (2.5 and 5 μg/mouse, intra-CA1) or nicotine (0.3 and 0.5 μg/mouse, intra-CA1) with an ineffective dose of ethanol (0.25 g/kg) significantly restored the retrieval and induced ethanol state-dependent memory. Pre-test intra-CA1 injection of the muscarinic receptor antagonist, atropine (4 and 8 μg/mouse, intra-CA1) or the nicotinic receptor antagonist, mecamylamine (2 and 4 μg/mouse, intra-CA1) 5 min before the administration of ethanol (1 g/kg, i.p.) dose dependently inhibited ethanol state-dependent memory. Pre-test intra-CA1 administration of physostigmine (0.5, 2.5 and 5 μg/mouse), atropine (2, 4 and 8 μg/mouse), nicotine (0.1, 0.3 and 0.5 μg/mouse) or mecamylamine (1, 2 and 4 μg/mouse) alone cannot affect memory retention. These findings implicate the involvement of a dorsal hippocampal cholinergic mechanism in ethanol state-dependent memory and also it can be concluded that there may be a cross-state dependency between ethanol and acetylcholine.     

Nicotinic acetylcholine receptors of the ventral tegmental area are involved in mediating morphine-state-dependent learning

In the present study, the possible role of nicotinic acetylcholine (nACh) receptors of the ventral tegmental area (VTA) on morphine-state-dependent learning was studied in adult male Wistar rats. As a model of memory, a step-through type passive avoidance task was used. All animals were bilaterally implanted with chronic cannulae in the VTA, trained using a 1 mA foot shock, and tested 24 h after training to measure step-through latency. Post-training subcutaneous (s.c.) injection of morphine (0.5–5 mg/kg) dose-dependently reduced the step-through latency, showing morphine-induced amnesia. Amnesia induced by post-training morphine was significantly reversed by pre-test administration of morphine (2.5–5 mg/kg, s.c.) and induced morphine-state-dependent learning. Pre-test injection of nicotine (0.25–1 μg/rat) into the VTA plus an ineffective dose of morphine (0.5 mg/kg) significantly restored the memory retrieval. It should be noted that pre-test intra-VTA injection of the same doses of nicotine (0.25–1 μg/rat) alone cannot affect memory retention. Furthermore, pre-test intra-VTA injection of the nicotinic acetylcholine receptor antagonist, mecamylamine (1–3 μg/rat) 5 min before the administration of morphine (5 mg/kg, s.c.) dose-dependently inhibited morphine-state-dependent learning. Pre-test injection of the higher dose of mecamylamine (3 μg/rat) into the VTA by itself decreased the step-through latency and induced amnesia. On the other hand, mecamylamine (0.5 and 1 μg/rat, intra-VTA) reversed the effect of nicotine on morphine response. The results indicate that nACh receptors in the VTA participate in the modulation of morphine-induced recovery of memory, on the test day.     

Post-training infusion of glutamate into the bed nucleus of the stria terminalis enhanced inhibitory avoidance memory: An effect involving norepinephrine

This study examined an interaction between glutamate and norepinephrine in the bed nucleus of the stria terminalis (BNST) in modulating affective memory formation. Male Wistar rats with indwelling cannulae in the BNST were trained on a one-trial step-through inhibitory avoidance task and received pre- or post-training intra-BNST infusion of glutamate, norepinephrine or their antagonists. Results of the 1-day test indicated that post-training intra-BNST infusion of dl-2-amino-5-phosphonovaleric acid (APV) impaired retention in a dose- and time-dependent manner, while infusion of glutamate had an opposite effect. Co-infusion of 0.2 μg glutamate and 0.02 μg norepinephrine resulted in marked retention enhancement by summating non-apparent effects of the two drugs given at a sub-enhancing dose. The amnesic effect of 5.0 μg APV was ameliorated by 0.02 μg norepinephrine, while the memory enhancing effect of 1.0 μg glutamate was attenuated by 5.0 μg propranolol. These findings suggest that training on an inhibitory avoidance task may alter glutamate neurotransmission, which by activating NMDA receptors releases norepinephrine to modulate memory formation via β adrenoceptors in the BNST.     

Effects of Posttraining Intrahippocampal Injections of Platelet-Activating Factor and PAF Antagonists on Memory

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 μg/0.5 μl), lyso-PAF (1.0 μg/0.5 μl), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 μg/0.5 μl), the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 μg/0.5 μl), or vehicle (50% DMSO in 0.9% saline; 0.5 μl). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 μg) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 μg) and BN 50730 (5.0 or 10 μg) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.     

Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats

Learning and memory deficits occur in diabetes mellitus. Although the pathogenesis of cognitive impairment in diabetes has not been fully elucidated, factors such as metabolic impairments, vascular complications and oxidative stress are thought to play possible roles. Here we investigated the effect of chronic treatment with vitamin C (50 mg/kg, p.o), vitamin E (100 mg/kg, p.o) and both together on passive avoidance learning (PAL) and memory in male Wistar control and diabetic rats. Treatments were begun at the onset of hyperglycemia. Passive avoidance learning was assessed 30 days later. Retention was tested 24 h after training. At the end, animals were weighed and blood samples were drawn for plasma glucose measurement. Diabetes caused impairment in acquisition and retrieval processes of PAL and memory. The combination of vitamin C and E improved learning and memory in controls and reversed learning and memory deficits in diabetic rats. Combined treatment also affected the body weight and plasma glucose level of diabetic treated animals compared to untreated diabetic animals. Hypoglycemic effects and antioxidant properties of the vitamins may be involved in the nootropic effect of such treatment. These results show that combined treatment with vitamins C and E improved PAL and memory of control rats. In addition, combined vitamins administration to rats for 30 days from onset of diabetes alleviated the negative influence of diabetes on learning and memory. Therefore, combined vitamins treatment may provide a new potential alternative for prevention of impaired cognitive functions associated with diabetes and may warrant further clinical study.     

Complete recovery of olfactory associative learning by activation of 5-HT4 receptors after dentate granule cell damage in rats

Bilateral intradentate injections of 3.0 μg of colchicine induced a substantial loss of granule cells and damage to the overlying pyramidal cell layer in region CA1 in adult male Long-Evans rats. All rats with such lesions showed a significant associative learning deficit in an olfactory discrimination task, while being unimpaired in the procedural component of this task. Injection of a partial selective 5-HT₄ agonist (SL65.0155; 0.01 mg/kg, i.p., vs. saline) before the third of six training sessions enabled complete recovery of associative learning performance in the lesioned rats. Activation of 5-HT₄ receptors by a selective agonist such as SL65.0155 might therefore provide an opportunity to reduce learning and memory deficits associated with temporal lobe damage, and could be useful for the symptomatic treatment of memory dysfunctions related to pathological aging such as Alzheimer’s disease.     

Differential effects of beta-adrenergic receptor blockade in basolateral amygdala or insular cortex on incidental and associative taste learning

The importance of central β-adrenergic system has been essentially investigated in aversive/emotional learning tasks. However, recent data suggest that the β-adrenergic system is also required for incidental taste learning. In the present study we evaluated in rats whether β-adrenergic receptor activity is required for taste habituation, an incidental taste learning, and also for conditioned taste aversion (CTA) learning, an associative learning. To address this issue, a low dose of the β-adrenergic antagonist propranolol was infused before learning in either the basolateral amygdala (BLA) or the insular cortex (IC), two forebrain areas reported to play a key role in taste memory formation. Incidental taste learning was assessed using a single presentation of the sweet taste saccharin 0.1%, which is sufficient to increase saccharin consumption (relative to water baseline) during a second presentation. CTA was assessed by pairing the first saccharin 0.1% presentation with a delayed gastric malaise, thus causing a decrease in saccharin consumption (relative to water baseline) during a second presentation. Propranolol infusion in BLA (1 μg/0.2μl) or IC (2.5 μg/0.5 μl) before the first taste exposure impaired incidental taste learning but did not affect CTA. These results highlight the important role played by the β-adrenergic receptor activation in cortical and amygdaloid structures during taste learning. Moreover, they are the first to suggest that incidental learning is more sensitive to blockade of noradrenergic system than associative learning.     

Medial prefrontal cortex infusions of bupivacaine or AP-5 block extinction of amphetamine conditioned place preference

The present experiments used reversible lesion techniques and intra-mPFC infusions of the n-methyl d-aspartate (NMDA) receptor antagonist d,l-2-amino-5-phosphonovaleric acid (AP-5) to examine the role of the mPFC in extinction of an amphetamine conditioned place preference (CPP). Following initial training and testing for an amphetamine (2 mg/kg) CPP, adult male Long–Evans rats were given extinction trials that were identical to training, except in the absence of peripheral amphetamine injections. Immediately prior to each extinction trial, rats received intra-mPFC infusions of the anesthetic drug bupivacaine (0.75% solution/0.5 μl), AP-5 (1.25, 2.5, 5.0 μg/0.5 μl), or saline. Following extinction training, rats were given a second CPP test session. Rats receiving intra-mPFC infusions of saline displayed extinction of CPP behavior. In contrast, intra-mPFC infusions of bupivacaine or AP-5 (2.5, 5.0 μg) blocked CPP extinction. The findings indicate (1) the mPFC mediates extinction of approach behavior to drug-associated environmental contexts, and (2) NMDA receptor blockade within the mPFC is sufficient to block extinction of amphetamine CPP behavior.     

Apodemus sylvaticus (LOXT) is a suitable mouse strain for testing spatial memory retention in the Morris water maze

Information on the difference in cognitive function between laboratory and wild-caught mice is anecdotal and this question has not been systematically studied. Moreover, studying a wild-caught mouse strain per se may add information to the repertoire of mouse strains available. We aimed to study spatial memory in a wild mouse strain (Apodemus sylvaticus, AS) as compared to two individual laboratory mouse strains.Male AS (n = 20), CD1 (n = 19) and C57BL/6J mice (n = 19), 12–14 weeks old, were used in the experiments. The Morris water maze (MWM) was used for determination of spatial memory and time spent in the target quadrant at time points 5 (D5) and 12 days (D12) was evaluated. During the acquisition phase latency to reach the platform and path length to reach the platform was evaluated.Following four training days on day 5 (D5), time spent in the target quadrant was highest in AS > CD1 > C57BL/6J (P < 0.006). On day 12 (D12), time spent in the target quadrant was significantly higher in AS than in both other strains (P < 0.001).All animals learned the task and during the acquisition phase, latency to reach the platform as well as path length decreased significantly in AS.It is concluded that the AS is the most suitable strain for the evaluation of spatial memory in the MWM and is presenting with memory retention superior to laboratory mouse strains CD1 and C57BL/6J.     

Enhancement of the Post-training Cholinergic Tone Antagonizes the Impairment of Retention Induced by a Nitric Oxide Synthase Inhibitor in Mice

The present experiments examined the role of the central cholinergic system in the memory impairment induced by post-training administration of a nitric oxide synthase (NOS) inhibitor in mice. Male Swiss mice received a one-trial inhibitory avoidance training (0.8 mA, 50 Hz, 1-s footshock) followed immediately by an ip injection of the NOS inhibitor -N^G-nitroarginine methyl ester ( -NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of -NAME results in memory impairment for the inhibitory avoidance task. The effects of -NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, sc) administered 30 min after the NOS inhibitor. Further, -NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg, sc) when given 30 min after -NAME. The peripherally acting anticholinesterase neostigmine (150 μg/kg, sc) did not modify the memory-impairing effects of -NAME. These findings suggest that the memory impairment following post-training administration of a NOS inhibitor is mediated, at least in part, by a reduction of the activity of central muscarinic cholinergic mechanisms and are consistent with our previous view that nitric oxide may be involved in post-training neural processes underlying the storage of newly acquired information.     

The Effects of Muscarinic Cholinergic Receptor Blockade in the Rat Anterior Cingulate and Prelimbic/Infralimbic Cortices on Spatial Working Memory

Previous findings indicate that cholinergic input to the medial prefrontal cortex may modulate mnemonic processes. The present experiment determined whether blockade of muscarinic cholinergic receptors in the rodent anterior cingulate and prelimbic/infralimbic cortices impairs spatial working memory. In a 12-arm radial maze, a working memory for spatial locations task was employed using a continuous recognition go/no-go procedure. Rats were allowed to enter 12 arms for a reinforcement. Of the 12 arm presentations, 3 or 4 arms were presented for a second time in a session that did not contain a reinforcement. The number of trials between the first and second presentations of an arm ranged from 0 to 6 (lags). Infusions of scopolamine (1, 5, and 10 μg), a muscarinic cholinergic antagonist, into the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, significantly impaired spatial working memory in a lag- and dose-dependent manner. The deficit induced by scopolamine (10 μg) was attenuated by concomitant intraprelimbic/infralimbic injections of oxotremorine (2 μg), a muscarinic cholinergic agonist. A separate group of rats was tested on a successive spatial discrimination task. Injections of scopolamine (1, 5, and 10 μg) into the prelimbic/infralimbic cortices did not impair performance on the spatial discrimination task. These findings suggest that muscarinic transmission in the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, is important for spatial working memory.     

Stria Terminalis Lesions Attenuate Memory Enhancement Produced by Intracaudate Nucleus Injections of Oxotremorine

The present study examined the role of the stria terminalis in modulating the memory enhancement produced by posttraining intracaudate nucleus injection of oxotremorine. Male Sprague–Dawley rats with either sham operations or bilateral lesions of the stria terminalis (ST) were trained on a one-trial inhibitory-avoidance task and received a unilateral posttraining intracaudate injection of either a buffer vehicle or the cholinergic agonist oxotremorine (0.3 μg/0.5 μl) into a medial region of the caudate nucleus innervated by the ST. Intracaudate injection of oxotremorine improved memory in sham-operated rats. Although ST lesions did not affect retention in rats given intracaudate injections of the buffer vehicle, ST lesions attenuated the memory enhancement produced by posttraining intracaudate injection of oxotremorine. In view of anatomical evidence indicating that amygdalostriatal projections are nonreciprocol, the present findings suggest that amygdalaoutputvia the ST is essential for memory enhancement produced by intracaudate injection of oxotremorine.     

Increasing acetylcholine levels in the hippocampus or entorhinal cortex reverses the impairing effects of septal GABA receptor activation on spontaneous alternation

Intra-septal infusions of the γ-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 μL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 μg/μL for the hippocampus; 7.5 μg/μL or 1.875 μg/0.25 μL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.     

Amygdala and “emotional” modulation of the relative use of multiple memory systems

The basolateral amygdala modulates the cognitive and habit memory processes mediated by the hippocampus and caudate nucleus, respectively. The present experiments used a plus-maze task that can be acquired using either hippocampus-dependent “place” learning or caudate-dependent “response” learning to examine whether peripheral or intra-basolateral amygdala injection of anxiogenic drugs would bias rats towards the use of a particular memory system. In Experiment 1, adult male Long–Evans rats were trained to swim from the same start point to an escape platform located in a consistent goal arm, and received pre-training peripheral injections of the α₂-adrenoceptor antagonists yohimbine (2.5 or 5.0 mg/kg), RS 79948-197 (0.05, 0.1, or 0.2 mg/kg), or vehicle. On a drug-free probe trial from a novel start point administered 24 h following acquisition, vehicle treated rats predominantly displayed hippocampus-dependent place learning, whereas rats previously treated with yohimbine (2.5, 5.0 mg/kg) or RS 79948-197 (0.1 mg/kg) predominantly displayed caudate-dependent response learning. In Experiment 2, rats receiving pre-training intra-basolateral amygdala infusions of RS 79948-197 (0.1 μg/0.5 μl) also predominantly displayed response learning on a drug-free probe trial. The findings indicate (1) peripheral injections of anxiogenic drugs can influence the relative use of multiple memory systems in a manner that favors caudate-dependent habit learning over hippocampus-dependent cognitive learning, and (2) intra-basolateral amygdala infusion of anxiogenic drugs is sufficient to produce this modulatory influence of emotional state on the use of multiple memory systems.     

Intraseptal Flumazenil Enhances, while Diazepam Binding Inhibitor Impairs, Performance in a Working Memory Task

GABA_A/benzodiazepine receptors in the medial septum modulate the activity of cholinergic neurons that innervate the hippocampus. Injection of benzodiazepine (BDZ) agonists into the medial septum impairs working memory performance and decreases high-affinity choline transport (HAChT) in the hippocampus. In contrast, intraseptal injection of the BDZ antagonist flumazenil increases HAChT and prevents the memory deficits induced by systemic BDZs. The present studies attempted to further characterize the behavioral effects of medial septal injections of flumazenil to an endogenous negative modulator of the GABA_A/BDZ receptor complex, diazepam binding inhibitor (DBI). Male Sprague–Dawley rats were cannulated to study the effects of intraseptal injections of these BDZ ligands on spatial working memory, anxiety-related behaviors in the elevated plus maze, and on general locomotor activity. Intraseptal flumazenil (10 nmol/0.5 μl) produced a delay-dependent enhancement of DNMTS performance after an 8-h, but not a 4-h, delay interval. This promnestic dose of flumazenil had no effect on locomotor activity and did not produce changes in measures of anxiety on the plus maze. Intraseptal injection of DBI had no effect (8 nmol/0.5 μl) or slightly impaired (4 nmol/0.5 μl) DNMTS radial maze performance following an 8-h delay, without producing changes in locomotion or plus maze behavior. These data demonstrate that flumazenil has a unique profile of activity in enhancing working memory following intraseptal injection.     

On modal μ-calculus with explicit interpolants

This paper deals with the extension of Kozen's μ-calculus with the so-called “existential bisimulation quantifier”. By using this quantifier one can express the uniform interpolant of any formula of the μ-calculus. In this work we provide an explicit form for the uniform interpolant of a disjunctive formula and see that it belongs to the same level of the fixpoint alternation hierarchy of the μ-calculus than the original formula. We show that this result cannot be generalized to the whole logic, because the closure of the third level of the hierarchy under the existential bisimulation quantifier is the whole μ-calculus. However, we prove that the first two levels of the hierarchy are closed. We also provide the μ-logic extended with the bisimulation quantifier with a complete calculus.     

Motivationally neutral stimulation of the nucleus basalis induces specific behavioral memory

The cholinergic system has been implicated in learning and memory. The nucleus basalis (NB) provides acetylcholine (ACh) to the cerebral cortex. Pairing a tone with NB stimulation (NBstm) to alter cortical state induces both associative specific tuning plasticity in the primary auditory cortex (A1) and associative specific auditory behavioral memory. NB-induced memory has major features of natural memory that is induced by pairing a tone with motivational reinforcers, e.g., food or shock, suggesting that the cholinergic system may be a “final common pathway” whose activation promotes memory storage. Alternatively, NB stimulation might itself be motivationally significant, either rewarding or punishing. To investigate these alternatives, adult male rats (n = 7) first formed a specific NB-induced memory (CS = 8.0 kHz, 2.0 s paired with NBstm, ISI = 1.8 s, 200 trials), validated by post-training (24 h) frequency generalization gradients (1–15 kHz) of respiration interruption that were specific to the CS frequency. Thereafter, they received the same level of NBstm that had induced memory, while confined to one quadrant of an arena, and later tested for place-preference, i.e., avoidance or seeking of the quadrant of NBstm. This NBstm group exhibited neither preference for nor against the stimulated quadrant, compared to sham-operated subjects (n = 7). The findings indicate that specific associative memory can be induced by direct activation of the NB without detectable motivational effects of NB stimulation. These results are concordant with a memory-promoting role for the nucleus basalis that places it “downstream” of motivational systems, which activate it to initiate the storage of the current state of its cholinergic targets.     

The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex

Stress hormones released by an experience can modulate memory strength via the basolateral amygdala, which in turn acts on sites of memory storage such as the cerebral cortex [McGaugh, J. L. (2004). The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annual Review of Neuroscience, 27, 1–28]. Stimuli that acquire behavioral importance gain increased representation in the cortex. For example, learning shifts the tuning of neurons in the primary auditory cortex (A1) to the frequency of a conditioned stimulus (CS), and the greater the level of CS importance, the larger the area of representational gain [Weinberger, N. M. (2007). Associative representational plasticity in the auditory cortex: A synthesis of two disciplines. Learning & Memory, 14(1–2), 1–16]. The two lines of research suggest that BLA strengthening of memory might be accomplished in part by increasing the representation of an environmental stimulus. The present study investigated whether stimulation of the BLA can affect cortical memory representations. In male Sprague–Dawley rats studied under urethane general anesthesia, frequency receptive fields were obtained from A1 before and up to 75 min after the pairing of a tone with BLA stimulation (BLAstm: 100 trials, 400 ms, 100 Hz, 400 μA [±16.54]). Tone started before and continued after BLAstm. Group BLA/1.0 (n = 16) had a 1 s CS–BLAstm interval while Group BLA/1.6 (n = 5) has a 1.6 s interval. The BLA/1.0 group did develop specific tuning shifts toward and to the CS, which could change frequency tuning by as much as two octaves. Moreover, its shifts increased over time and were enduring, lasting 75 min. However, group BLA/1.6 did not develop tuning shifts, indicating that precise CS–BLAstm timing is important in the anesthetized animal. Further, training in the BLA/1.0 paradigm but stimulating outside of the BLA did not produce tuning shifts. These findings demonstrate that the BLA is capable of exerting highly specific, enduring, learning-related modifications of stimulus representation in the cerebral cortex. These findings suggest that the ability of the BLA to alter specific cortical representations may underlie, at least in part, the modulatory influence of BLA activity on strengthening long-term memory.     

Memory Consolidation for Contextual and Auditory Fear Conditioning Is Dependent on Protein Synthesis, PKA, and MAP Kinase

Fear conditioning has received extensive experimental attention. However, little is known about the molecular mechanisms that underlie fear memory consolidation. Previous studies have shown that long-term potentiation (LTP) exists in pathways known to be relevant to fear conditioning and that fear conditioning modifies neural processing in these pathways in a manner similar to LTP induction. The present experiments examined whether inhibition of protein synthesis, PKA, and MAP kinase activity, treatments that block LTP, also interfere with the consolidation of fear conditioning. Rats were injected intraventricularly with Anisomycin (100 or 300 μg), Rp-cAMPS (90 or 180 μg), or PD098059 (1 or 3 μg) prior to conditioning and assessed for retention of contextual and auditory fear memory both within an hour and 24 hr later. Results indicated that injection of these compounds selectively interfered with long-term memory for contextual and auditory fear, while leaving short-term memory intact. Additional control groups indicated that this effect was likely due to impaired memory consolidation rather than to nonspecific effects of the drugs on fear expression. Results suggest that fear conditioning and LTP may share common molecular mechanisms.