Posttraining Electrical Stimulation of Vagal Afferents with Concomitant Vagal Efferent Inactivation Enhances Memory Storage Processes in the Rat

Peripherally administered or released substances that modulate memory storage, but do not freely enter the brain, may produce their effects on memory by activating peripheral receptors that send messages centrally through the vagus nerve. Indeed, vagus nerve stimulation enhances memory performance, although it is unclear whether this effect is due to the activation of vagal afferents or efferents. To eliminate the possible influence of descending fibers on memory storage processes, rats were implanted with cuff electrode/catheter systems along the left cervical vagus. Forty-eight hours following surgery, each animal received a 3.0-μl infusion (1.0 μl/min) of either lidocaine hydrochloride (75.0 mM) or isotonic saline below the point of stimulation. Animals were then trained 10 min later on an inhibitory-avoidance task with a 0.75-mA, 1.0-s foot shock. Sham stimulation or vagus nerve stimulation (0.5-ms biphasic pulses; 20.0 Hz; 30 s; 0.2, 0.4, or 0.8 mA) was administered immediately after training. Memory, tested 24 h later, was enhanced by stimulation whether descending vagus nerve fibers were inactivated or not. Both lidocaine- and saline-infused groups showed an intensity-dependent, inverted-U-shaped pattern of retention performance, with the greatest effect observed for 0.4 mA (U= 9,p< .05, andU= 7,p< .01, respectively). Additionally, animals that received lidocaine infusions, but no vagus nerve stimulation, showed impaired memory compared to the performance of saline-infused control animals (U= 11,p< .05). Together, these findings suggest that vagal afferents carry messages about peripheral states that lead to the modulation of memory storage and that the memory-enhancing effect produced by vagus nerve stimulation is not mediated via the activation of vagal efferents.     

Effects of posttraining treatments in the posterior cingulate cortex on short- and long-term memory for inhibitory avoidance in rats

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in the caudal region of the posterior cingulate cortex. After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock) and received, right after training, a 0.5-microl infusion of vehicle (phosphate-buffered saline, pH 7.4), of the GABA(A) receptor agonist muscimol (0.1 or 0.5 microg), of the cAMP-dependent protein kinase (PKA) stimulant Sp-cAMPS (0.1 or 0.5 microg), or of the PKA inhibitor Rp-cAMPS (0.1 or 0.5 microg). Animals were tested twice, 1.5 h and, again, 24 h after training, in order to examine the effects of these agents on short- and long-term memory, respectively. Muscimol (0.5 but not 0.1 microg) hindered retention for both short- and long-term memory (p <.05). Rp-cAMPS (0.1 or 0.5 microg) hindered retention for short-term memory (p <.05). In addition, these animals showed lower, but not significantly lower, latencies than controls in the test session for long-term memory (p >.10). A trend toward an amnesic effect on long-term memory was also observed after Sp-cAMPS infusion at 0.1 microg (p <.10). These results show that strong stimulation of GABAergic synapses in the caudal region of the rat posterior cingulate cortex right after training impairs short- and long-term memory (the latter less dramatically). The same occurs by inhibiting PKA activity with regard to STM and possibly to LTM.     

Distinct mechanisms underlying memory modulation after the first and the second session of two avoidance tasks

Rats were subjected to three consecutive sessions, one session per day, of either a step-down inhibitory avoidance task using a 60-Hz. 0.3-mA footshock, or a two-way active avoidance task using 20 presentations of a 5-s, 1-kHz tone and a 0.3-mA footshock. After either the first or the second training session animals received an intraperitoneal injection of ACTH (0.2 microgram/kg), epinephrine-HCl (5.0 micrograms/kg), or naloxone-HCl (0.8 mg/kg). All these treatments caused memory facilitation on both tasks when administered after the first training session. When administered after the second training session only ACTH and adrenaline were effective, on both tasks. As previous physiological and pharmacological reports point to the activation of the brain beta-endorphin system after the first, but not the second, session of a task, we propose that (a) memory facilitation by naloxone depends on the previous activation of the brain beta-endorphin system; and (b) memory facilitation due to ACTH or epinephrine does not depend on the opioid activity, so their effects are expressed after both the first and the second training sessions. It was also observed that the enhancement of performance in the second training session due to post-training facilitatory treatments carried over to the test session. These results suggest that some form of consolidation occurs both after the first and after the second training session.     

Beta-endorphin enhancement of retrieval in a three-session paradigm

Rats were submitted to three consecutive sessions, one session per day, of step-down inhibitory avoidance task (60-Hz, 0.3-mA footshock) or of two-way active avoidance task (25 trials of a 5-s, 1-kHz tone and a 0.4-mA footshock). Animals received intraperitoneal (ip) injections of saline or beta-endorphin (2.0 micrograms/kg) before or after the second session and before the third session. beta-Endorphin given before either the second or the third session improved retention of both tasks, while its administration after the second session had no effect upon performance on both tasks. In Experiment 2, it was shown that rats receiving naloxone (0.2 mg/kg) ip after the first session did not exhibit the enhancement of retrieval by beta-endorphin administration before the second session, so a non-state-dependent improvement of retrieval by the opioid seems to be unlikely. In view of these results we can propose that the presession retrieval enhancing effect of beta-endorphin is due to an endogenous state dependency on the opioid that can be expressed either in the second or in the third session of aversive tasks.     

Post-training memory facilitation blocks extinction but not retroactive interference

Rats were trained in a step-down inhibitory avoidance task using a 0.2-mA footshock and tested 6 h later. Exposure to a session of extinction (animals placed on the box where they had been trained and left to explore it freely for 100.0 s without footshocks) or to a series of 10 tones presented in another box, in the dark, 2 h after training, hindered retention test performance. The immediate post-training ip administration of epinephrine (5.0 micrograms/kg), ACTH-(1-24) (0.2 microgram/kg), or lysine-vasopressin (10.0 micrograms/kg) facilitated retention test performance and cancelled the effect of extinction, but not the retroactive interference caused by exposure to the tones. These results support the concept that post-training facilitation induced by the hormones is due to a strengthening of the memory trace left by the avoidance task, whereas the retroactive interference caused by the tones occurs independently from that process and is more likely due to the incorporation of postevent information.     

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.     

Consolidation and long-term retention of an implanted behavioral memory

Hypothesized circuitry enabling information storage can be tested by attempting to implant memory directly in the brain in the absence of normal experience. Previously, we found that tone paired with activation of the cholinergic nucleus basalis (NB) does induce behavioral memory that shares cardinal features with natural memory; it is associative, highly specific, rapidly formed, consolidates and shows intermediate retention. Here we determine if implanted memory also exhibits long-term consolidation and retention. Adult male rats were first tested for behavioral responses (disruption of ongoing respiration) to tones (1-15 kHz), yielding pre-training behavioral frequency generalization gradients. They next received 3 days of training with a conditioned stimulus (CS) tone (8.0 kHz, 70 dB, 2s) either paired (n=7) or unpaired (n=6) with moderate electrical stimulation of the nucleus basalis (～ 65 μA, 100 Hz, 0.2s, co-terminating with CS offset). Testing for long-term retention was performed by obtaining post-training behavioral frequency generalization gradients 24h and 2 weeks after training. At 24h post-training, the Paired group exhibited specific associative behavioral memory, manifested by larger responses to the CS frequency band than the Unpaired group. This memory was retained 2 weeks post-training. Moreover, 2 weeks later, the specificity and magnitude of memory had become greater, indicating that the implanted memory had undergone consolidation. Overall, the results demonstrate the validity of NB-implanted memory for understanding natural memory and that activation of the cholinergic nucleus basalis is sufficient to form natural associative memory.     

Behavioral memory induced by stimulation of the nucleus basalis: Effects of contingency reversal

Specific behavioral associative memory induced by stimulation of the cortically-projecting cholinergic nucleus basalis (NB) is dependent on intrinsic acetylcholine and shares with natural memory such features as associativity, specificity, rapid formation, consolidation and long-term retention. Herein, we examined extinction and the effects of stimulus pre-exposure. Two groups of adult male rats (n = 4 each) were first tested for behavioral responses (disruption of ongoing respiration) to tones (1–15 kHz), constituting a pre-training behavioral frequency generalization gradient (BFGG). They next received a first session of training, 200 trials of a tone (8.00 kHz, 70 dB, 2 s) either paired with electrical stimulation of the NB (100 Hz, 0.2 s, ～67 μA, NBstm) (group IP) or unpaired (group IU). Twenty-four hours later, they were tested for behavioral memory by obtaining post-training BFGGs. Then the contingencies were reversed yet another 24 h later; the IP group received tone and NBstm unpaired and the IU group received them paired. A final set of generalization gradients was obtained the next day. All stimuli were presented with subjects under state control indexed by regular respiration. Tested 24 h post-initial training, the IP group developed specific associative behavioral memory indicated by increased responses only to CS-band frequencies, while the IU group did not. After subsequent training with unpaired stimuli, the IP group exhibited experimental extinction. Furthermore, after initial exposure to the CS and NBstm unpaired, the IU group exhibited a tendency toward reduced conditioning to CS/NBstm pairing and a significant increase in latency of conditioned responses. The present findings provide additional support for the hypothesis that engagement of the NB is sufficient to induce natural associative memory and suggest that activation of the NB may be a normal component in the formation of natural associative memory.     

Retrieval effects of beta-endorphin and naloxone, and the novelty-induced antinociception in the developing rat

Three experiments were conducted to assess the retrieval effects of a single dose of beta-endorphin and of naloxone, and of the novelty-induced antinociception response in the developing rat. Wistar rats 30, 45, 60, and 90 days old from our breeding stock were used. Animals were trained and tested, with a 24-h interval between sessions, in a two-way active avoidance task (using 20 presentations of a 5-s, 1-kHz tone and a 0.4-mA footshock) or in a step-down inhibitory avoidance task (using a 60-Hz, 0.2-mA footshock). Saline (1.0 ml/kg), beta-endorphin (2.0 microgram/Kg), or naloxone (0.8 mg/kg), was administered ip immediately after training, and saline or beta-endorphin was administered 6 min before testing. The retrieval enhancing effects of post-training naloxone and pretest beta-endorphin, and the retrieval impairing effect of post-training beta-endorphin, were consistently observed only in 60- and 90-day-old rats, on both tasks. In a third experiment, another group of naive rats was placed for 2 min in a novel environment (the shuttlebox) and nociception was assessed by the tail-flick method. Novelty-induced antinociception was observed only for 60- and 90-day-old rats, and this response was cancelled by naloxone given 6 min before exposure to novelty. These results suggest that both the retrieval effects of naloxone and beta-endorphin, in the doses used, and the novelty-induced antinociception response, which are possibly dependent on the activity of hypothalamic beta-endorphin system, become established between 45 and 60 days postnatal in the rat.     

On how passive is inhibitory avoidance

Rats were trained in a step-down inhibitory avoidance task using a 25 X 25-cm platform and either a 0.3- or a 0.8-mA training footshock. Immediately after training retrieval was good in all animals; but at 24 h there was a decline in the group trained with 0.3-mA footshock. This decline was not observed in animals submitted to an immediate retrieval test and then tested again at 24 h. Thus, the immediate retrieval test apparently served the purpose of a rehearsal. A considerable degree of activity (rearing, ambulation, sticking the head out of the platform) was observed in test sessions. Activity scores were lower in the animals trained with the 0.8-mA footshock. The amount of activity, however, was unrelated to retrieval performance (i.e., to test session step-down latency).     

Sensory memory consolidation observed: Increased specificity of detail over days

Memories are usually multidimensional, including contents such as sensory details, motivational state and emotional overtones. Memory contents generally change over time, most often reported as a loss in the specificity of detail. To study the temporal changes in the sensory contents of associative memory without motivational and emotional contents, we induced memory for acoustic frequency by pairing a tone with stimulation of the cholinergic nucleus basalis. Adult male rats were first tested for behavioral responses (disruption of ongoing respiration) to tones (1–15 kHz), yielding pre-training behavioral frequency generalization gradients (BFGG). They next received three days of training consisting of a conditioned stimulus (CS) tone (8.00 kHz, 70 dB, 2 s) either Paired (n = 5) or Unpaired (n = 5) with weak electrical stimulation (～48 μA) of the nucleus basalis (100 Hz, 0.2 s, co-terminating with CS offset). Testing for behavioral memory was performed by obtaining post-training BFGGs at two intervals, 24 and 96 h after training. At 24 h post-training, the Paired group exhibited associative behavioral memory manifested by significantly larger responses to tone than the Unpaired group. However, they exhibited no specificity in memory for the frequency of the tonal CS, as indexed by a flat BFGG. In contrast, after 96 h post-training the Paired group did exhibit specificity of memory as revealed by tuned BFGGs with a peak at the CS-band of frequencies. This increased detail of memory developed due to a loss of response to lower and higher frequency side-bands, without any change in the absolute magnitude of response to CS-band frequencies. These findings indicate that the sensory contents of associative memory can be revealed to become more specific, through temporal consolidation in the absence of non-sensory factors such as motivation and emotion.     

Water can induce better spatial memory performance than food in radial maze learning by rats1

Abstract: Two experiments were carried out to test the differential effects of hunger and thirst on memory performance. In Experiment 1, two groups of rats were exposed to an original radial‐maze task and then to a 30‐min retention‐memory task. The food‐deprived group completed the original task more quickly than the water‐deprived group, but the thirsty group mastered the memory task more quickly than the hungry group (p < 0.01). In Experiment 2, deprivation conditions were changed from the original to the memory task. The food‐water group completed the memory task more rapidly than the water‐food group (p < 0.05). Thirst proved to constitute a more favorable condition for retention‐memory learning. The applicability of several theories is discussed.     

The Clinical Plus the Experimental Emphasis in Elementary Work in Psychology

Forty-two Ss were run in one experimental and in two control conditions. The Ss recalled a short story immediately after reading it and again 24 hours later. All Ss were monitored on two physiological variables during reading. The experimental group was subjected to a 0.2-second delayed auditory feedback in the middle section of the story. One control group received no special treatment; the other received shock at the point in the story at which the experimental group received delayed auditory feedback. Both the experimental group and the control group that received shock showed marked changes in GSR measurements during the reading of the middle section of the story. The immediate memory of the story was significantly poorer for the experimental group as contrasted with that for each of the control groups. For accuracy of delayed memory, there were no significant differences among the three groups.     

Very long-term retention of a novel

This study investigated the very long-term retention of a full-length novel originally studied as part of a university undergraduate course. One hundred and forty former students completed three tests designed to assess retention of Charles Dickens' Hard Times. Retention intervals ranged from 3 to 39 months. Subjects' responses when they were asked to report their most vivid and enduring memory of the novel were consistent with story grammar models which claim that components of a story which are higher in a hierarchy are remembered better than those lower in the hierarchy. A free recall test of the names and roles of the characters in the novel found that retention of both declined rapidly in the first few months following acquisition, that names were forgotten more quickly than roles, and that retention of both had stabilized above baseline before the longest retention interval. These data are interpreted in terms of a schema account of memory retention, in which retention of schematic knowledge (roles), but not non-schematic knowledge (names) can be mediated by abstract knowledge structures. The results of a fact verification test showed that memory for events of high importance in the novel was better than memory for events of low importance, consistent with models that suggest that texts and stories are represented hierarchically in memory. Confidence ratings also declined over time and showed that subjects generally assessed the accuracy of their responses correctly. The significant predictors of memory for the novel were retention interval and the mark obtained on a coursework essay on Hard Times.     

Long-term consolidation and retention of learning-induced tuning plasticity in the auditory cortex of the guinea pig.

The major goal of this study was to determine whether classical conditioning produces long-term neural consolidation of frequency tuning plasticity in the auditory cortex. Local field potentials (LFPs) were obtained from chronically implanted adult male Hartley guinea pigs that were divided into conditioning (n = 4) and sensitization control (n = 3) groups. Tuning functions were determined in awake subjects for average LFPs (approximately 0.4 to 36.0 kHz, -20 to 80 dB) immediately before training as well as 1 h and 1, 3, 7, and 10 days after training; sensitization subjects did not have a 10-day retention test. Conditioning consisted of a single session of 30 to 45 trials of a 6-s tone (CS, 70 dB) that was not the best frequency (BF, peak of a tuning curve), followed by a brief leg shock (US) at CS offset. Sensitization control animals received the same density of CS and US presentations unpaired. Heart rate recordings showed that the conditioning group developed conditioned bradycardia, whereas the sensitization control group did not. Local field potentials in the conditioning group, but not in the sensitization group, developed tuning plasticity. The ratio of responses to the CS frequency versus the BF were increased 1 h after training, and this increase was retained for the 10-day period of the study. Both tuning plasticity and retention were observed across stimulus levels (10-80 dB). Most noteworthy, tuning plasticity exhibited consolidation (i.e., developed greater CS-specific effects across retention periods), attaining asymptote at 3 days. The findings indicate that LFPs in the auditory cortex have three cardinal features of behavioral memory: associative tuning plasticity, long-term retention, and long-term consolidation. Potential cellular and subcellular mechanisms of LFP tuning plasticity and long-term consolidation are discussed.     

The effects of a target–stimulus reminder on performance in a novel object recognition task

The effects of original training-stimulus pre-test reminders were examined in a novel object recognition (NOR) task. NOR is a task that examines memory for complex stimuli, and is driven by the rats’ tendency to spend significantly more time exploring novel objects over those previously experienced. In this task, a delay is imposed between a training experience during which the animal is allowed to investigate a set of identical objects, and a later test exposure where the animal encounters one of the original objects and a novel object with which it has had no previous experience. Experiment 1 demonstrated that performance at 24 h is significantly worse than at an immediate delay (1 min). In the second experiment, it was demonstrated that neither a 10-s nor a 30-s reminder treatment, in the absence of training, resulted in a level of preference for novelty, a measure of memory for the original object, that was significantly greater than chance. Experiment 3 illustrated significant performance effects of a 30-s training stimulus reminder administered 15 min prior to test with a 24-h retention interval. The final experiment illustrated that the additional 30-s of object exposure is effective in enhancing performance only if it occurs shortly prior to test. Animals receiving the additional 30-s immediately following training did not experience such beneficial effects. It was concluded, based upon these results, that pre-test training-stimulus reminders in this task produce effects similar to those seen in more traditional tasks of learning and memory.     

The contribution of disengagement to temporal discriminability

The present study examines the idea that time-based forgetting of outdated information can lead to better memory of currently relevant information. This was done using the visual arrays task, along with a between-subjects manipulation of both the retention interval (1?s vs. 4?s) and the time between two trials (1?s vs. 4?s). Consistent with prior work [Shipstead, Z., &; Engle, R. W. (2013). Interference within the focus of attention: Working memory tasks reflect more than temporary maintenance. Journal of Experimental Psychology: Learning, Memory, and Cognition, 39, 277–289; Experiment 1], longer retention intervals did not lead to diminished memory of currently relevant information. However, we did find that longer periods of time between two trials improved memory for currently relevant information. This replicates findings that indicate proactive interference affects visual arrays performance and extends previous findings to show that reduction of proactive interference can occur in a time-dependent manner.     

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.     

Short- and Long-Term Implicit Memory in Aging and Alzheimer's Disease

ABSTRACT

Implicit memory processes were investigated via picture naming in healthy young and older adults and in persons with mild Alzheimer's disease (AD). Repetition priming in picture-naming was intact in all groups over the course of a short retention interval (seconds), and only the AD group revealed a deficit over a longer interval (72 hours). In addition, the AD group showed impaired procedural memory, with no benefit of practice on picture-naming. Impaired long-term priming was related to severity of AD. Both theoretical and methodological implications are discussed.     

Differential effects of post-training muscimol and AP5 infusions into different regions of the cingulate cortex on retention for inhibitory avoidance in rats.

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in four different coordinates of the cingulate cortex: (1) the anterior cingulate (AC), (2) the rostral region of the posterior cingulate (RC), (3) the upper portion of the caudal region of the posterior cingulate (UC), and (4) the lower portion of the caudal region of the posterior cingulate (LC). After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock). Either immediately, or 90 or 180 min after training, animals received a 0.5-microl infusion of vehicle (phosphate buffer, pH 7.4), of muscimol (0.5 microg), or of AP5 (5.0 microg). Retention testing was carried out 24 h after training. Muscimol was amnestic when given into any of the three coordinates of the posterior cingulate cortex 90 min after training, and when given into LC immediately post-training. In addition, AP5 was amnestic when given into UC 90 min post-training, but not when given into any other region and/or at any other time. None of the treatments had any effect when given into AC. The results suggest that memory processing of the inhibitory avoidance task is regulated by the posterior but not by the anterior cingulate cortex, through muscimol-sensitive synapses, relatively late after training. AP5-sensitive synapses appear to play a very limited role in these processes, restricted to UC.