Consolidation Of Inhibitory Avoidance Memory Research Articles

The G protein-coupled estrogen receptor (GPER) regulates recognition and aversively–motivated memory in male rats

Estrogens, particularly 17β-estradiol (estradiol, E2), regulate memory formation. E2 acts through its intracellular receptors, estrogen receptors (ER) ERα and ERβ, as well as a recently identified G protein-coupled estrogen receptor (GPER). Although the effects of E2 on memory have been investigated, studies examining the effects of GPER stimulation are scarce. Selective GPER agonism improves memory in ovariectomized female rats, but little information is available regarding the effects of GPER stimulation in male rodents. The aim of the present study was to investigate the effects of the GPER agonist, G1, on consolidation and reconsolidation of inhibitory avoidance (IA) and object recognition (OR) memory in male rats. Animals received vehicle, G1 (15, 75, 150 µg/kg; i.p.), or the GPER antagonist G15 (100 µg/kg; i.p.) immediately after training, or G1 (150 µg/kg; i.p.) 3 or 6 h after training. To investigate reconsolidation, G1 was administered immediately after IA retention Test 1. Results indicated that G1 administered immediately after training at the highest dose enhanced both OR and IA memory consolidation, while GPER blockade immediately after training impaired OR. No effects of GPER stimulation were observed when G1 was given 3 or 6 h after training or after Test 1. The present findings provide evidence that GPER is involved in the early stages of memory consolidation in both neutral and emotional memory tasks in male adult rats.

Rottlerin, BDNF, and the impairment of inhibitory avoidance memory.

As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 μg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 μg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD).

Imbalance in cerebral protein homeostasis: Effects on memory consolidation

The long-standing hypothesis that memory consolidation is dependent upon de novo protein synthesis is based primarily on the amnestic effects of systemic administration of protein synthesis inhibitors (PSIs). Early experiments on mice showed that PSIs produced interference with memory consolidation that was dependent on the doses of PSIs, on the interval between drug injection and training, and, importantly, on the degree and duration of protein synthesis inhibition in the brain. Surprisingly, there is a conspicuous lack of information regarding the relationship between the duration of protein synthesis inhibition produced by PSIs and memory consolidation in the rat, one of the species most widely used to study memory processes. We found that, in the male rat, a single injection of cycloheximide, a commonly used PSI, produced a significant imbalance in protein homeostasis: an early inhibition of protein synthesis that lasted for at least one hour, followed by hyperproduction of proteins that lasted three days. We evaluated memory consolidation of inhibitory avoidance trained with either low or high intensity of foot-shock at the peaks of protein synthesis inhibition and protein hyperproduction. We found that, independent of the moment of training, the low-foot-shock groups showed amnesia, while the high-foot-shock groups displayed optimal memory performance. These results indicate that memory consolidation of relatively weak training is impaired by the inhibition or hyperproduction of protein synthesis, and that intense training overcomes this dysregulation of protein homeostasis allowing for memory formation probably through non-genomic mechanisms.

D-Lys-3-GHRP-6 impairs memory consolidation and downregulates the hippocampal serotonin HT1A, HT7 receptors and glutamate GluA1 subunit of AMPA receptors

Antagonism of the functional ghrelin receptors impairs memory formation, but the underlying mechanisms are not well-known. We aimed to evaluate the effect of intracerebral injection of a ghrelin receptor antagonist (D-Lys-3-GHRP-6) on memory consolidation in the inhibitory avoidance task and on the gene expression levels of serotonin HT1A and HT7 receptors, glutamate GluN1 subunit of the NMDA and GluA1 subunit of the AMPA receptors and calcium/calmodulin kinase II-α in the hippocampus of rats. Thirty adult male rats were implanted with cannulas in their lateral ventricles. Three groups of animals (n=5) received D-Lys-3-GHRP-6 (0.5 and 5nM) or saline immediately post-training. Twenty-four hours later, memory retrieval was assessed. Three additional groups of animals (n=5) received D-Lys-3-GHRP-6 (0.5 and 5nM) or saline, but animals in these groups were decapitated, and their hippocampus was removed, 24 hours thereafter. The target gene expression levels were measured using a quantitative real-time PCR method. D-Lys-3-GHRP-6 impaired memory consolidation. Meanwhile, it led to a significant downregulation of the mRNA expression levels of the hippocampal serotonin HT1A and HT7 receptors and glutamate GluA1 subunit of the AMPA receptors, but could not affect that of GluN1 subunit of the NMDA receptors and CaMKII-α. It seems that part of the impairing effect of D-Lys-3-GHRP-6 on inhibitory avoidance memory consolidation might be due to a decrease in the expression of serotonin HT1A and HT7 receptors and glutamate AMPA receptors in the hippocampus of rats.

Exposure to GSM 900-MHz mobile radiation impaired inhibitory avoidance memory consolidation in rat: Involvements of opioidergic and nitrergic systems

The use of mobile phones is increasing, and the main health concern is the possible deleterious effects of radiation on brain functioning. The present study aimed to examine the effects of exposure to a global system for mobile communication (GSM) with mobile phones on inhibitory avoidance (IA) memory performance as well as the involvement of endogenous opioids and nitric oxide (NO) in this task. Male Wistar rats, 10–12 weeks old, were used. The results showed that four weeks of mobile phone exposure impaired IA memory performance in rats. The results also revealed that post-training, but not pre-training, as well as pre-test intracerebroventricular (i.c.v.) injections of naloxone (0.4, 4 and 40 ng/rat), dose-dependently recovered the impairment of IA memory performance induced by GSM radiation. Additionally, the impairment of IA memory performance was completely recovered in the exposed animals with post-training treatment of naloxone (40 ng/rat) plus pre-test i.c.v. injections of L-arginine (100 and 200 nmol/rat). However, pre-test i.c.v. injections of L-NAME (10 and 20 nmol/rat), impaired IA memory performance in the animals receiving post-training naloxone (40 ng/rat). In the animals receiving post-training naloxone treatment, the impairment of IA memory performance due to pre-test i.c.v. injections of L-NAME was recovered by the pre-test co-administration of L-arginine. It was concluded that the recovery from impairment of IA memory in GSM-exposed animals with post-training naloxone treatment was the result of blockade of the opioidergic system in early memory consolidation as well as activation of the nitrergic system in the retrieval phase of memory.

Post-training reversible disconnection of the ventral hippocampal-basolateral amygdaloid circuits impairs consolidation of inhibitory avoidance memory in rats.

The ventral hippocampus (VH) and the basolateral amygdala (BLA) are both crucial in inhibitory avoidance (IA) memory. However, the exact role of the VH–BLA circuit in IA memory consolidation is unclear. This study investigated the effect of post-training reversible disconnection of the VH–BLA circuit in IA memory consolidation. Male Wistar rats with implanted guide cannulae were trained with a one-trial IA task, then received immediate intracerebral injections of muscimol or saline, and were tested 24 h later. Muscimol injection into the bilateral BLA, or the unilateral VH and contralateral BLA, but not the unilateral VH and ipsilateral BLA, significantly decreased the retention latencies (versus saline treatment). The results suggest that the VH–BLA circuit could be an important circuit to modulate consolidation of IA memory in rats.

Administration of a Histone Deacetylase Inhibitor into the Basolateral Amygdala Enhances Memory Consolidation, Delays Extinction, and Increases Hippocampal BDNF Levels.

Gene expression related to the formation and modification of memories is regulated epigenetically by chromatin remodeling through histone acetylation. Memory formation and extinction can be enhanced by treatment with inhibitors of histone deacetylases (HDACs). The basolateral amygdala (BLA) is a brain area critically involved in regulating memory for inhibitory avoidance (IA). However, previous studies have not examined the effects of HDAC inhibition in the amygdala on memory for IA. Here we show that infusion of an HDAC inhibitor (HDACi), trichostatin A (TSA), into the BLA, enhanced consolidation of IA memory in rats when given at 1.5, 3, or 6 h posttraining, but not when the drug was infused immediately after training. In addition, intra-BLA administration of TSA immediately after retrieval delayed extinction learning. Moreover, we show that intra-BLA TSA in rats given IA training increased the levels of brain-derived neurotrophic factor in the dorsal hippocampus, but not in the BLA itself. These findings reveal novel aspects of the regulation of fear memory by epigenetic mechanisms in the amygdala.

Comparison of 5-HT3 or 5-HT4 agents function into the prelimbic area on passive avoidance memory consolidation

Growing evidence suggests that serotonin plays an important role in learning and memory and all its receptors might be implicated in this process. The present study aimed at investigating and comparing the possible involvement of 5-HT 3 and 5-HT 4 receptor (R) agonists/antagonists upon consolidation of inhibitory avoidance memory in the pre-limbic (PL) area. Bilateral intra-PL microinjections of m-CPBG (m-Chlorophenylbiguanide hydrochloride: a selective 5-HT 3 R agonist; 0.1 μg/rat), Y-25130 (a selective 5-HT 3 R antagonist; 0.1 μg/rat), RS67333 (a potent and highly selective 5-HT 4 R partial agonist; 0.5 μg/rat) and RS23597-190 (a selective 5-HT 4 R antagonist; 0.5 μg/rat) were performed immediately after training. The step-through inhibitory avoidance (IA) task was used to memory assessment in adult male Sprague-Dawley rats. Our data revealed that the post-training intra-PL microinjection of m-CPBG relative to saline and Y-25130 decreased inhibitory avoidance memory consolidation in the PL area. On the contrary, RS67333 increased IA memory consolidation in comparison to saline and RS23597-190. In addition, there was also a significant difference between the effects of m-CPBG and RS67333 on IA memory consolidation in the PL area. M-CPBG induced reduction of IA memory consolidation, while RS67333 increased it. However, Y-25130 compared to RS23597-190 did not show any significant difference. All above interventions did not alter locomotor activity. This study indicated that local direct agonist activation of 5-HT 3 Rs induced the reduction of IA memory consolidation, opposed to the local direct agonist activation of 5-HT 4 Rs, which mediated enhancement of IA memory consolidation. It can be proposed that 5-HT 3 Rs in comparison to 5-HT4Rs may be inversely involved in modulation of IA memory consolidation in the PL.

Histone deacetylase inhibition prevents the impairing effects of hippocampal gastrin-releasing peptide receptor antagonism on memory consolidation and extinction

Hippocampal gastrin-releasing peptide receptors (GRPR) regulate memory formation and extinction, and disturbances in GRPR signaling may contribute to cognitive impairment associated with neurodevelopmental disorders. Histone acetylation is an important epigenetic mechanism that regulates gene expression involved in memory formation, and histone deacetylase inhibitors (HDACis) rescue memory deficits in several models. The present study determined whether inhibiting histone deacetylation would prevent memory impairments produced by GRPR blockade in the hippocampus. Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or the HDACi sodium butyrate (NaB) shortly before inhibitory avoidance (IA) training, followed by an infusion of either SAL or the selective GRPR antagonist RC-3095 immediately after training. In a second experiment, the infusions were administered before and after a retention test trial that served as extinction training. As expected, RC-3095 significantly impaired consolidation and extinction of IA memory. More importantly, pretraining administration of NaB, at a dose that had no effect when given alone, prevented the effects of RC-3095. In addition, the combination of NaB and RC-3095 increased hippocampal levels of the brain-derived neurotrophic factor (BDNF). These findings indicate that HDAC inhibition can protect against memory impairment caused by GRPR blockade.

The consolidation of inhibitory avoidance memory in mice depends on the intensity of the aversive stimulus: The involvement of the amygdala, dorsal hippocampus and medial prefrontal cortex

Several studies using inhibitory avoidance models have demonstrated the importance of limbic structures, such as the amygdala, dorsal hippocampus and medial prefrontal cortex, in the consolidation of emotional memory. However, we aimed to investigate the role of the amygdala (AMG), dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) of mice in the consolidation of step-down inhibitory avoidance and whether this avoidance would be conditioned relative to the intensity of the aversive stimulus. To test this, we bilaterally infused anisomycin (ANI-40μg/μl, a protein synthesis inhibitor) into one of these three brain areas in mice. These mice were then exposed to one of two different intensities (moderate: 0.5mA or intense: 1.5mA) in a step-down inhibitory avoidance task. We found that consolidation of both of the aversive experiences was mPFC dependent, while the AMG and DH were only required for the consolidation of the intense experience. We suggest that in moderately aversive situations, which do not represent a severe physical risk to the individual, the consolidation of aversive experiences does not depend on protein synthesis in the AMG or the DH, but only the mPFC. However, for intense aversive stimuli all three of these limbic structures are essential for the consolidation of the experience.

Synergistic effect between prelimbic 5-HT3 and CB1 receptors on memory consolidation deficit in adult male Sprague–Dawley rats: An isobologram analysis

The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague–Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5μg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1μg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1μg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005μg/rat) potentiated, while Y-25130 (0. 1μg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area.

TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition.

Relatively little is known about the requirement of signaling initiated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in the early phases of memory consolidation, as well as about its possible functional interactions with epigenetic mechanisms. Here we show that blocking TrkB in the dorsal hippocampus after learning or retrieval impairs retention of memory for inhibitory avoidance (IA). More importantly, the impairing effect of TrkB antagonism on consolidation was completely prevented by the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB). Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or NaB before training, followed by an infusion of either vehicle (VEH) or the selective TrkB antagonist ANA-12 immediately after training. In a second experiment, the infusions were administered before and after retrieval. ANA-12 after either training or retrieval produced a significant impairment in a subsequent memory retention test. Pretraining administration of NaB prevented the effect of ANA-12, although NaB given before retrieval did not alter the impairment resulting from TrkB blockade. The results indicate that inhibition of BDNF/TrkB in the hippocampus can hinder consolidation and reconsolidation of IA memory. However, TrkB activity is not required for consolidation in the presence of NaB, suggesting that a dysfunction in BDNF/TrkB signaling can be fully compensated by HDAC inhibition to allow hippocampal memory formation.

Involvement of the nucleus accumbens shell glutamatergic system in ACPA-induced impairment of inhibitory avoidance memory consolidation

Interactions between cannabinoid and glutamate systems have been demonstrated in some brain areas associated with mnemonic functions. This study investigates the effects of bilateral post-training intra-nucleus accumbens (NAc) shell administrations of glutamate NMDA receptor agents on memory impairment induced by cannabinoid CB1 receptor activation during a step-through inhibitory avoidance (IA) task. Our results showed post-training administration of ACPA (CB1 receptor agonist; 3ng/side) impairs IA memory consolidation, whereas AM251 (CB1 receptor antagonist; 0.3, 3 and 30ng/side), NMDA (0.3, 3 and 30ng/side), and d-AP7 (NMDA receptor antagonist; 3, 30 and 300ng/side) were ineffective. However, co-administration of AM251 (30ng/side) or NMDA (30ng/side) with ACPA (3ng/side) prevented the memory-impairing effect of ACPA. Meanwhile, co-administration of NMDA (30ng/side) and a subthreshold dose of ACPA (0.15ng/side) decreased memory consolidation. Moreover, post-training microinjection of AM251 (30ng/side) or d-AP7 (300ng/side) prevented memory impairment induced by co-administration of subthreshold doses of NMDA and ACPA. The data indicated that NMDA receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the NAc shell.

Functional Connectivity Changes during Consolidation of Inhibitory Avoidance Memory in Rats: A Manganese-Enhanced MRI Study

Consolidation of memory involves transfer of encoded information into a durable neural representation, but how this is transacted in the nervous system remains elusive. It has been proposed that memory consolidation is subserved by formation of a cell assembly due to coincidence of pre- and post-synaptic activity therein after learning. To capture such off-line changes, manganese-enhanced magnetic resonance imaging (MEMRI) was used to trace brain activity during the memory consolidation period. Male Wistar rats were trained on the one-trial inhibitory avoidance task and received intraventricular infusion of manganese ion shortly after training. The MEMRI taken 1 day later showed that brain areas including the prelimbic, insular and anterior pirifrom cortices of the learning group had significantly lower memory-related MEMRI signal than those of the control group. The functional network was revealed by correlating the MEMRI signals among regions followed by graph theoretical analysis. Learning sculpted the non-discriminative connectivity among many brain regions in the controls into a network in the trained rats with selected connectivity among regions implicated in inhibitory avoidance learning. The network could be organized into three clusters presumably subserving different functions. The results suggest that the brain prunes excessive functional connectivity in a cell assembly to consolidate new memory.

Histamine infused into basolateral amygdala enhances memory consolidation of inhibitory avoidance

The role of the basolateral amygdala (BLA) in the consolidation of aversive memory is well established. Here we investigate the involvement of the histaminergic system in BLA on this variable. Rats were chronically implanted with bilateral cannulae in the BLA and after recovery were trained in a one-trial step-down inhibitory avoidance task. Immediately after training histaminergic compounds either alone or in combination were infused through the cannulae. Memory was assessed in test sessions carried out 24 h after the training session. Post-training histamine (1-10 nmol; 0.5 μl/side) enhanced consolidation and the histamine H₃ receptor antagonist thioperamide (50 nmol; 0.5 μl/side) impaired memory consolidation. The effect was shared by the histamine N-methyltransferase inhibitor SKF-91844 (50 nmol; 0.5 μl/side) as well as by the H₃ receptor agonist imetit (10 nmol; 0.5 μl/side). The promnesic action of histamine was unaffected by the H₁ receptor antagonist pyrilamine (50 nmol; 0.5 μl/side). The H1 receptor agonist pyridylethylamine (10 nmol; 0.5 μl/side), the H₂ agonist dimaprit (10 nmol; 0.5 μl/side) and the H₂ antagonist ranitidine (50 nmol; 0.5 μl/side) were ineffective. Histaminergic compounds infused into the BLA had no effect on open-field or elevated plus-maze behaviour. The data show that histamine induces a dose-dependent mnemonic effect in rats and indicate that this reflects a role of endogenous histamine in the BLA mediated by H₃ receptors.

Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories

The neocortex is thought to be a distributed learning system that gradually integrates semantic information into the initial mnemonic representation rapidly formed by the hippocampus after acquisition. Nevertheless, an emerging view suggests that some cortical regions, in particular the medial prefrontal cortex (mPFC), may also have a role during the initial steps of memory consolidation as well as in the recall of recent memories. Here, we show that mPFC plays a critical role during the first few hours of inhibitory avoidance memory consolidation and is necessary for the normal retrieval of both recent and remote memories, supporting the idea that involvement of neocortical areas in memory processing is not restricted to the late post-training consolidation phase.

Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats

Memory consolidation studies, including those examining the role of the basolateral amygdala (BLA), have traditionally used techniques limited in their temporal and spatial precision. The development of optogenetics provides increased precision in the control of neuronal activity that can be used to address the temporal nature of the modulation of memory consolidation. The present experiments, therefore, investigated whether optogenetically stimulating and inhibiting BLA activity immediately after training on an inhibitory avoidance task enhances and impairs retention, respectively. The BLA of male Sprague-Dawley rats was transduced to express either ChR2(E123A) or archaerhodopsin-3 from the Halorubrum sodomense strain TP009 (ArchT). Immediately after inhibitory avoidance training, rats received optical stimulation or inhibition of the BLA, and 2 d later, rats' retention was tested. Stimulation of ChR2(E123A)-expressing neurons in the BLA using trains of 40-Hz light pulses enhanced retention, consistent with recording studies suggesting the importance of BLA activity at this frequency. Light pulses alone given to control rats had no effect on retention. Inhibition of ArchT-expressing neurons in the BLA for 15 min, but not 1 min, significantly impaired retention. Again, illumination alone given to control rats had no effect on retention, and BLA inhibition 3 h after training had no effect. These findings provide critical evidence of the importance of specific frequency patterns of activity in the BLA during consolidation and indicate that optogenetic manipulations can be used to alter activity after a learning event to investigate the processes underlying memory consolidation.

Cooperative interaction between the basolateral amygdala and ventral tegmental area modulates the consolidation of inhibitory avoidance memory

The aim of the current study was to examine the existence of a cooperative interaction between the basolateral nucleus of amygdala (BLA) and the ventral tegmental area (VTA) in inhibitory avoidance task. The BLA and the VTA regions of adult male Wistar rats were simultaneously cannulated and memory consolidation was measured in a step-through type inhibitory avoidance apparatus. Post-training microinjection of muscimol, a potent GABA-A receptor agonist (0.01-0.02 μg/rat), into the VTA impaired memory in a dose-dependent manner. Post-training intra-BLA microinjection of NMDA (0.02-0.04 μg/rat), 5 min before the intra-VTA injection of muscimol (0.02 μg/rat), attenuated muscimol-induced memory impairment. Microinjection of a NMDA receptor antagonist, D-AP5 (0.02-0.06 μg/rat) into the BLA inhibited NMDA effect on the memory impairment induced by intra-VTA microinjection of muscimol. On the other hand, post-training intra-BLA microinjection of muscimol (0.02-0.04 μg/rat) dose-dependently decreased step-through latency, indicating an impairing effect on memory. This impairing effect was however significantly attenuated by intra-VTA microinjection of NMDA (0.01-0.03 μg/rat). Intra-VTA microinjection of D-AP5 (0.02-0.08 μg/rat), 5 min prior to NMDA injection, inhibited NMDA response on the impairing effect induced by intra-BLA microinjection of muscimol. It should be considered that post-training microinjection of the same doses of NMDA or D-AP5 into the BLA or the VTA alone had no effect on memory consolidation. The data suggest that the relationship between the BLA and the VTA in mediating memory consolidation in inhibitory avoidance learning may be dependent on a cooperative interaction between the glutamatergic and GABAergic systems via NMDA and GABA-A receptors.

Activation of dopamine D1 receptors in the medial septum improves scopolamine-induced amnesia in the dorsal hippocampus

In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3μg/rat had no effect, but at dose of 0.5μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine.

Memory-enhancing intra-basolateral amygdala infusions of clenbuterol increase Arc and CaMKIIα protein expression in the rostral anterior cingulate cortex

Activation of β-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory through interactions with multiple memory systems. The cellular mechanisms for this interaction remain unresolved. Memory-modulating BLA manipulations influence expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc) in the dorsal hippocampus, and hippocampal expression of Arc protein is critically involved in memory consolidation and long-term potentiation. The present studies examined whether this influence of the BLA is specific to the hippocampus and to Arc protein. Like the hippocampus, the rostral portion of the anterior cingulate cortex (rACC) is involved in the consolidation of inhibitory avoidance (IA) memory, and IA training increases Arc protein in the rACC. Because the BLA interacts with the rACC in the consolidation of IA memory, the rACC is a potential candidate for further studies of BLA modulation of synaptic plasticity. The alpha isoform of the Calcium/Calmodulin-dependent protein kinase II (CaMKIIα) and the immediate early gene c-Fos are involved in long-term potentiation and memory. Both Arc and CaMKIIα proteins can be translated in isolated synapses, where the mRNA is localized, but c-Fos protein remains in the soma. To examine the influence of memory-modulating manipulations of the BLA on expression of these memory and plasticity-associated proteins in the rACC, male Sprague–Dawley rats were trained on an IA task and given intra-BLA infusions of either clenbuterol or lidocaine immediately after training. Findings suggest that noradrenergic stimulation of the BLA may modulate memory consolidation through effects on both synaptic proteins Arc and CaMKIIα, but not the somatic protein c-Fos. Furthermore, protein changes observed in the rACC following BLA manipulations suggest that the influence of the BLA on synaptic proteins is not limited to those in the dorsal hippocampus.