Cholinergic dependence of taste memory formation: evidence of two distinct processes

Learning the aversive or positive consequences associated with novel taste solutions has a strong significance for an animal's survival. A lack of recognition of a taste's consequences could prevent ingestion of potential edibles or encounter death. We used conditioned taste aversion (CTA) and attenuation of neophobia (AN) to study aversive and safe taste memory formation. To determine if muscarinic receptors in the insular cortex participate differentially in both tasks, we infused the muscarinic antagonists scopolamine at distinct times before or after the presentation of a strong concentration of saccharin, followed by either an i.p. injection of a malaise-inducing agent or no injection. Our results showed that blockade of muscarinic receptors before taste presentation disrupts both learning tasks. However, the same treatment after the taste prevents AN but not CTA. These results clearly demonstrate that cortical cholinergic activity participates in the acquisition of both safe and aversive memory formation, and that cortical muscarinic receptors seem to be necessary for safe but not for aversive taste memory consolidation. These results suggest that the taste memory trace is processed in the insular cortex simultaneously by at least two independent mechanisms, and that their interaction would determine the degree of aversion or preference learned to a novel taste.     

Long-term memory formation in the chick requires mobilization of ryanodine-sensitive intracellular calcium stores

Training chicks (Gallus domesticus) on a one-trial passive avoidance task results in transient and time-dependent enhanced increases in N-methyl-d-aspartate- or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-stimulated intracellular calcium concentration in synaptoneurosomes isolated from a specific forebrain region, the intermediate medial hyperstriatum ventrale. This increase could result from either calcium entry from the extracellular medium or from mobilization of intracellular calcium stores. We have therefore examined the effects of dantrolene, an inhibitor of calcium release from the intracellular ryanodine-sensitive store, on these processes. Dantrolene, 50 nmol per hemisphere injected intracerebrally 30 min pre- or 30 min posttraining, blocked longer term memory for the passive avoidance task, whereas memory for the task was unaffected when dantrolene was injected at earlier or later times. Preincubation of synaptoneurosomes, isolated from the intermediate hyperstriatum ventrale 10 min after training, with 100 nM dantrolene abolished the enhanced training-induced increase in intracellular calcium concentration elicited by 0.5 mM N-methyl-d-aspartate. By contrast, the training-induced enhancement of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate-stimulated increase in intracellular calcium concentration in synaptoneurosomes prepared 6 h posttraining was unaffected by preincubation with dantrolene, which was not amnestic at this time. Calcium release from ryanodine-sensitive intracellular stores may thus be a necessary stage in the early phase of the molecular cascade leading to the synaptic modulation required for long-term memory storage.     

Inhibition of passive-avoidance memory formation in the day-old chick by the opioid cytochrophin-4

Cytochrophin-4 (cyt-4), a tetrapeptide with opioid-like activity, caused amnesia when injected into chick forebrain 5 hr after passive-avoidance training. Bilateral injections of cyt-4 directly into the lobus parolfactorius (LPO) resulted in the chicks being amnesic for the training task 24 hr later, whereas unilateral injections of cyt-4 were effective only when injected into the right LPO. Cyt-4-induced amnesia was reversed by the general opioid antagonist, naloxone, indicating that cyt-4 was acting via an opioid receptor. The mu- and delta-opioid receptors (but not kappa-opioid or ORL(1)-receptors) have been shown to be involved in memory formation 5 hr after training (). Because an antagonist of the mu-opioid receptor inhibited memory, we attempted to reverse the effect of cyt-4 using mu-opioid receptor agonists. Met[enk] was unable to reverse the inhibition of memory formation by cyt-4 suggesting that the mu-opioid receptor is not involved in this effect. However endomorphin-2 (endo-2) reversed the effect of cyt-4. We further investigated the action of endo-2 using an irreversible antagonist of the mu-receptor, beta-funaltrexamine (beta-FAN), and found that endo-2 reversed beta-FAN-induced amnesia indicating that endo-2 was not acting on the mu-opioid receptor in the chick. Because unilateral injections of beta-FAN were not amnesic (bilateral injections were amnesic) this provided further evidence that the effect of cyt-4 was not mediated via the mu-opioid receptor. Coinjection of the delta-receptor agonist, (D-Pen(2), L-Pen(5))enkephalin (DPLPE), reversed the disruptive effect of cyt-4 on memory. However, memory modulation via the delta-opioid receptor was not lateralized to the right hemisphere suggesting that cyt-4 does not act via this receptor either. It was shown that an antagonist of the epsilon-opioid receptor inhibited memory at the 5 hr time point. We conclude that the epsilon-opioid receptor or an unidentified opioid receptor subtype could be involved in the action of cyt-4.     

Inhibition of short-term memory formation in the chick by blockade of extracellular glutamate uptake

Injection of monosodium glutamate (40nmol/hemisphere) into the intermediate hyperstriatum ventrale of the day-old chick inhibits the formation of short-term memory for a single trial learning that discriminates between colours of beads. These experiments showed that an excess of glutamate close to learning could be damaging to memory. In the present experiments we have blocked the normal reuptake of glutamate and suggest that glutamate release plays a role in normal learning. Removal of glutamate, released from presynaptic neurones during learning, is achieved by various neuronal and astrocytic glutamate transporters. By blocking the primarily astrocytic removal of glutamate by the injection of L-aspartic acid beta-hydroxamate, we effectively increased extrasynaptic levels of glutamate and inhibited short-term memory in a similar manner to central injection of 40nmol glutamate per hemisphere. These experiments suggest that glutamate release within 2.5min of the learning experience is an important feature of short-term memory formation.     

Maternal hen calls modulate memory formation in the day-old chick: the role of noradrenaline

Facilitation of memory for discriminative learning in young chicks is enhanced following exposure to a synthesized rhythmic auditory stimulus. Increased arousal, mediated by noradrenergic activation, is believed to underlie this effect. In this report we examine whether ethologically relevant rhythmic auditory stimuli produce the same noradrenaline-mediated memory enhancement in neonate chicks (Gallus gallus domesticus). Maternal hen attraction calls which contained a rhythmic pattern were found to facilitate retention. Intracerebral injection of noradrenaline or the beta(2)-adrenergic antagonist propranolol demonstrated that this enhancement is likely to be mediated by noradrenergic activation of central beta(2)-noradrenergic receptors. In contrast, a rhythmic alarm call inhibited retention. Subcutaneous injection of the alpha(1)-adrenergic antagonist prazosin revealed that this impairment may be due to higher arousal levels resulting in activation of alpha(1)-noradrenergic receptors. It is concluded that the maternal hen calls of domestic chickens can influence the memory ability of the offspring via noradrenaline release in the brain. The current data suggest that call meaning and rhythmicity interact to yield the appropriate levels of beta(2)-adrenergic activation required to facilitate retention for a discriminative task.     

Involvement of BDNF receptor TrkB in spatial memory formation

The N-methyl-D-aspartate (NMDA) receptors are involved in long-term potentiation (LTP), and are phosphorylated by several tyrosine kinases including a Src-family tyrosine kinase Fyn. Brain-derived neurotrophic factor (BDNF) is a neurotrophin, which also enhances hippocampal synaptic transmission and efficacy by increasing NMDA receptor activity. Here, we show that Fyn is a key molecule linking the BDNF receptor TrkB with NMDA receptors, which play an important role in spatial memory formation in a radial arm maze. Spatial learning induced phosphorylation of TrkB, Fyn, and NR2B, but not NR2A, in the hippocampus. Fyn was coimmunoprecipitated with TrkB and NR2B, and this association was increased in well-trained rats compared with control animals. Continuous intracerebroventricular infusion of PP2, a tyrosine kinase inhibitor, in rats delayed memory acquisition in the radial arm maze, but PP2-treated animals reached the same level of learning as the controls. The phosphorylation of Fyn and NR2B, but not TrkB, was diminished by PP2 treatment. Our findings suggest the importance of interaction between BDNF/TrkB signaling and NMDA receptors for spatial memory in the hippocampus.     

Alcohol beverage cues impair memory in high social drinkers

This study examined the influence of an alcohol beverage cue on memory processes in social drinkers. High and low drinking college students viewed a series of 15 pictures of common objects with the eighth picture either of an alcohol beverage or a soda. For high drinkers, free recall of the alcohol picture was enhanced, and memory for the pictures immediately following the cue was suppressed, relative to the series containing the soda picture. No such effects were observed for light drinkers. Apparently, alcohol cues affect attention and memory in heavy social drinkers. These results have important implications for theories of memory and attention, for explanations of addictive behaviour, and for effective prevention and treatment of alcoholism.     

Strain-dependent effects of post-training dopamine receptor agonists and antagonists on memory storage in mice.

Post-training administration of the selective D1 or D2 agonists SKF 38393 and LY 171555 dose dependently impairs retention of an inhibitory avoidance response in DBA/2 mice. In agreement, the selective D1 or D2 antagonists SCH 23390 and (-)-sulpiride improve retention. These effects are opposite to those observed in the C57BL/6 strain, as previously reported. Moreover, B6D2F1 hybrids present a response to SKF 38393, LY 171555, SCH 23390, and (-)-sulpiride that parallels that of the C57BL/6 strain, thus suggesting that the neural mechanisms underlying the effects of DA agonists or antagonists on memory processes may be inherited through a dominant mode of inheritance.     

Perirhinal cortex muscarinic receptor blockade impairs taste recognition memory formation

The relevance of perirhinal cortical cholinergic and glutamatergic neurotransmission for taste recognition memory and learned taste aversion was assessed by microinfusions of muscarinic (scopolamine), NMDA (AP-5), and AMPA (NBQX) receptor antagonists. Infusions of scopolamine, but not AP5 or NBQX, prevented the consolidation of taste recognition memory using attenuation of neophobia as an index. In addition, learned taste aversion in both short- and long-term memory tests was exclusively impaired by scopolamine. These data provide neurochemical support for the theory that cholinergic activity of the perirhinal cortex participates in the formation of the taste memory trace and that it is independent of the NMDA and AMPA receptor activity. These results support the idea that cholinergic neurotransmission in the perirhinal cortex is also essential for acquisition and consolidation of taste recognition memory.     

Motor interference does not impair the memory consolidation of imagined movements

The present study aimed to investigate whether an interference task might impact the sleep-dependent consolidation process of a mentally learned sequence of movements. Thirty-two participants were subjected to a first training session through motor imagery (MI) or physical practice (PP) of a finger sequence learning task. After 2 h, half of the participants were requested to perform a second interfering PP task (reversed finger sequence). All participants were finally re-tested following a night of sleep on the first finger sequence. The main findings revealed delayed performance gains following a night of sleep in the MI group, i.e. the interfering task did not alter the consolidation process, by contrast to the PP group. These results confirm that MI practice might result in less retroactive interference than PP, and further highlight the relevance of the first night of sleep for the consolidation process following MI practice. These data might thus contribute to determine in greater details the practical implications of mental training in motor learning and rehabilitation.     

Exposure to a rhythmic auditory stimulus facilitates memory formation for the passive avoidance task in the day-old chick.

Previous research regarding the beneficial effects of auditory stimuli on learning and memory in humans has been inconsistent. In the current study, day-old chicks were used to reduce the impact of individual differences on responses. Chicks were trained on a passive avoidance task and exposed to various auditory stimuli. Exposure to a complex rhythmic sequence for 1 min strongly facilitated chicks' long-term memory. The optimal time of presentation of the stimulus was between 10 min before and 20 min after training. Moreover, the enhancing effect was not generalized to the other auditory stimuli tested. It is suggested that this effect may be due to arousal because arousal hormones are critical to long-term memory formation. This study indicates that the temporal characteristics and type of stimulus may be important considerations when investigating the effects of auditory stimuli on cognitive functioning.     

Insulin receptor substrate 2 is a negative regulator of memory formation

Insulin has been shown to impact on learning and memory in both humans and animals, but the downstream signaling mechanisms involved are poorly characterized. Insulin receptor substrate-2 (Irs2) is an adaptor protein that couples activation of insulin- and insulin-like growth factor-1 receptors to downstream signaling pathways. Here, we have deleted Irs2, either in the whole brain or selectively in the forebrain, using the nestin Cre- or D6 Cre-deleter mouse lines, respectively. We show that brain- and forebrain-specific Irs2 knockout mice have enhanced hippocampal spatial reference memory. Furthermore, NesCreIrs2KO mice have enhanced spatial working memory and contextual- and cued-fear memory. Deletion of Irs2 in the brain also increases PSD-95 expression and the density of dendritic spines in hippocampal area CA1, possibly reflecting an increase in the number of excitatory synapses per neuron in the hippocampus that can become activated during memory formation. This increase in activated excitatory synapses might underlie the improved hippocampal memory formation observed in NesCreIrs2KO mice. Overall, these results suggest that Irs2 acts as a negative regulator on memory formation by restricting dendritic spine generation.     

The effects of adenosine receptor agonists and antagonists on morphine state-dependent memory of passive avoidance

Pretraining administration of morphine (5 mg/kg, intraperitonically) in a step-down passive avoidance task led to state-dependent learning with impaired retrieval on the test day that was dose-dependently restored by pretest administration of morphine (0.5, 1, 3, and 5 mg/kg). This restoration was reversible by pretest naloxone administration. Pretest administration of adenosine receptor antagonists theophylline or 8-phenyltheophylline (8-PT) did not alter morphine-induced amnesia. However, both the antagonists inhibited the restoration of memory by pretest morphine (5 mg/kg). Adenosine A(1) receptor agonists N(6)-cyclohexyladenosine (CHA) or N(6)-phenylisopropyladenosine (R-PIA) only at the higher doses used, and adenosine A(2) receptor agonist 5'-N-ethylcarboxaminoadenosine (NECA), at all doses used, decreased morphine-induced amnesia in a dose-dependent manner. Pretest administration of low doses of CHA, R-PIA, or NECA significantly showed additive effects with low dose pretest morphine (1 mg/kg) in restoring memory. The promnestic effects of high-dose CHA and R-PIA were inhibited by theophylline or 8-PT but not by naloxone. The additive effects of low-dose CHA or R-PIA and morphine were inhibited by theophylline, 8-PT, or a higher dose of naloxone. The promnestic effect of NECA and its additive effect with low-dose morphine were both inhibited by theophylline and naloxone but not by 8-PT. It is concluded that activation of the adenosinergic system, through both A(1) and A(2) receptors, can reverse morphine-induced amnesia and is involved in morphine state of memory.     

Electrolytic lesions of dorsal CA3 impair episodic-like memory in rats

Episodic memory is the ability to recollect one's past experiences occurring in an unique spatial and temporal context. In non-human animals, it is expressed in the ability to combine "what", "where" and "when" factors to form an integrated memory system. During the search for its neural substrates, the hippocampus has attracted a lot of attentions. Yet, it is not yet possible to induce a pure episodic-like memory deficit in animal studies without being confounded by impairments in the spatial cognition. Here, we present a lesion study evidencing direct links between the hippocampus CA3 region and the episodic-like memory in rats. In a spontaneous object exploration task, lesioned rats showed no interaction between the temporal and spatial elements in their memory associated with the objects. In separate tests carried out subsequently, the same animals still expressed abilities to process spatial, temporal, and object recognition memory. In conclusions, our results support the idea that the hippocampus CA3 has a particular status in the neural mechanism of the episodic-like memory system. It is responsible for combining information from different modules of cognitive processes.     

State orientation and memory load impair prospective memory performance in older compared to younger persons

A modified event-based paradigm of prospective memory was applied to investigate intention initiation in older and younger participants under high versus low memory load (subsequent episodic word recall vs. recognition). State versus action orientation, a personality dimension related to intention enactment, was also measured. State-oriented persons show a superiority effect for the storage of intentions in an explicit format but have a paradoxical deficit in their actual enactment. We predicted an interaction between aging, personality, and memory load, with longer intention-initiation latencies and higher omission rates for older state-oriented participants under high memory load. Results were consistent with predictions and are interpreted according to current personality and prospective memory models of aging.     

Glycine(B) receptor antagonists and partial agonists prevent memory deficits in inhibitory avoidance learning

Activation of N-methyl-d-aspartate (NMDA) receptors has been hypothesized to mediate certain forms of learning and memory. This hypothesis is based on the ability of competitive and uncompetitive NMDA receptor antagonists to disrupt learning. We investigated the effects of glycine site antagonists and partial agonists on deficits of acquisition (learning) and consolidation (memory) in a single trial inhibitory avoidance learning paradigm. Posttraining administration of either hypoxia (exposure to 7% oxygen) or the convulsant drug pentylenetetrazole (PTZ) (45 mg/kg) to mice impaired consolidation without producing neuronal cell death. Pretreatment with the competitive glycine antagonist 7-chlorokynurenic acid (7KYN) and the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+)HA-966 prevented memory deficits induced by hypoxia and PTZ, but did not affect scopolamine-induced learning impairment. In addition, ACPC prevented consolidation deficits evoked by a nonexcitotoxic concentration of l-trans-pyrrolidine-2, 4-dicarboxylate, a competitive inhibitor of glutamate transport that increases extracellular levels of glutamate. Moreover, (+)HA-966, 7KYN, and ACPC facilitated both acquisition and consolidation of inhibitory avoidance training, an effect that was dose-dependent and reversed by glycine. These results indicate that memory deficits induced by both hypoxia and PTZ involve NMDA receptor activation. Furthermore, the present findings demonstrate that glycine site antagonists and partial agonists prevent memory deficits of inhibitory avoidance learning by affecting consolidation, but not acquisition processes.     

Septal co-infusions of glucose with a GABAB agonist impair memory

Septal infusions of glucose exacerbate memory deficits produced by co-infusions of drugs that increase gamma-aminobutyric acid (GABA)(A) receptor activity. To further understand the interaction between glucose and GABA, this experiment tested whether glucose would also potentiate spatial working memory deficits produced by septal infusions of the GABA(B) receptor agonist baclofen. Fifteen minutes prior to assessing spontaneous alternation (SA), male Sprague-Dawley derived rats were given septal infusions of vehicle, glucose (33 nmol), baclofen (0.1 nmol), or glucose combined with baclofen in one solution. Septal co-infusions of glucose with baclofen, at doses that individually had no effect, significantly impaired SA. Thus, the memory-impairing effects of glucose are observed with either GABA(A) or GABA(B) receptor ligands. This raises the possibility that glucose may impair memory by increasing synaptic levels of GABA and subsequent activation of these different receptor subtypes. These effects of glucose could contribute to the memory-impairing effects of hyperglycemia.     

Lipopolysaccharide-induced experimental immune activation does not impair memory functions in humans

Reconsolidation studies have led to the hypothesis that memory, when labile, would be modified in order to incorporate new information. This view has reinstated original propositions suggesting that short-term memory provides the organism with an opportunity to evaluate and rearrange information before storing it, since it is concurrent with the labile state of consolidation. The Chasmagnathus associative memory model is used here to test whether during consolidation it is possible to change some attribute of recently acquired memories. In addition, it is tested whether these changes in behavioral memory features can be explained as modifications on the consolidating memory trace or as a consequence of a new memory trace. We show that short-term memory is, unlike long-term memory, not context specific. During this short period after learning, behavioral memory can be updated in order to incorporate new contextual information. We found that, during this period, the cycloheximide retrograde amnesic effect can be reverted by a single trial in a new context. Finally, by means of memory sensitivity to cycloheximide during consolidation and reconsolidation, we show that the learning of a new context (CS) during this short-term memory period builds up a new memory trace that sustains the behavioral memory update.