Delayed Nonmatching-to-sample Research Articles

Effects of environmental and pharmacological manipulations on a novel delayed nonmatching-to-sample ‘working memory’ procedure in unrestrained rhesus monkeys

BackgroundWorking memory is a domain of ‘executive function.’ Delayed nonmatching-to-sample (DNMTS) procedures are commonly used to examine working memory in both human laboratory and preclinical studies. New methodThe aim was to develop an automated DNMTS procedure maintained by food pellets in rhesus monkeys using a touch-sensitive screen attached to the housing chamber. Specifically, the DNMTS procedure was a 2-stimulus, 2-choice recognition memory task employing unidimensional discriminative stimuli and randomized delay interval presentations. ResultsDNMTS maintained a delay-dependent decrease in discriminability that was independent of the retention interval distribution. Eliminating reinforcer availability during a single delay session or providing food pellets before the session did not systematically alter accuracy, but did reduce total choices. Increasing the intertrial interval enhanced accuracy at short delays. Acute Δ9-THC pretreatment produced delay interval-dependent changes in the forgetting function at doses that did not alter total choices. Acute methylphenidate pretreatment only decreased total choices. Comparison with existing methodsAll monkeys were trained to perform NMTS at the 1s training delay within 60 days of initiating operant touch training. Furthermore, forgetting functions were reliably delay interval-dependent and stable over the experimental period (∼6 months). ConclusionsConsistent with previous studies, increasing the intertrial interval improved DNMTS performance, whereas Δ9-THC disrupted DNMTS performance independent of changes in total choices. Overall, the touchscreen-based DNMTS procedure described provides an efficient method for training and testing experimental manipulations on working memory in unrestrained rhesus monkeys.

Monkey pulvinar neurons fire differentially to snake postures.

There is growing evidence from both behavioral and neurophysiological approaches that primates are able to rapidly discriminate visually between snakes and innocuous stimuli. Recent behavioral evidence suggests that primates are also able to discriminate the level of threat posed by snakes, by responding more intensely to a snake model poised to strike than to snake models in coiled or sinusoidal postures (Etting and Isbell 2014). In the present study, we examine the potential for an underlying neurological basis for this ability. Previous research indicated that the pulvinar is highly sensitive to snake images. We thus recorded pulvinar neurons in Japanese macaques (Macaca fuscata) while they viewed photos of snakes in striking and non-striking postures in a delayed non-matching to sample (DNMS) task. Of 821 neurons recorded, 78 visually responsive neurons were tested with the all snake images. We found that pulvinar neurons in the medial and dorsolateral pulvinar responded more strongly to snakes in threat displays poised to strike than snakes in non-threat-displaying postures with no significant difference in response latencies. A multidimensional scaling analysis of the 78 visually responsive neurons indicated that threat-displaying and non-threat-displaying snakes were separated into two different clusters in the first epoch of 50 ms after stimulus onset, suggesting bottom-up visual information processing. These results indicate that pulvinar neurons in primates discriminate between poised to strike from those in non-threat-displaying postures. This neuronal ability likely facilitates behavioral discrimination and has clear adaptive value. Our results are thus consistent with the Snake Detection Theory, which posits that snakes were instrumental in the evolution of primate visual systems.

Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys

Human aging is characterized by declines in cognition and fine motor function as well as improved emotional regulation. In men, declining levels of testosterone (T) with age have been implicated in the development of these age-related changes. However, studies examining the effects of T replacement on cognition, emotion and fine motor function in older men have not provided consistent results. Rhesus monkeys (Macaca mulatta) are excellent models for human cognitive aging and may provide novel insights on this issue. We tested 10 aged intact male rhesus monkeys (mean age=19, range 15–25) on a battery of cognitive, motor and emotional tasks at baseline and under low or high T experimental conditions. Their performance was compared to that of 6 young males previously tested in the same paradigm (Lacreuse et al., 2009; Lacreuse et al., 2010). Following a 4-week baseline testing period, monkeys were treated with a gonadotropin releasing hormone agonist (Depot Lupron, 200μg/kg) to suppress endogenous T and were tested on the task battery under a 4-week high T condition (injection of Lupron+T enanthate, 20mg/kg, n=8) or 4-week low T condition (injection of Lupron+oil vehicle, n=8) before crossing over to the opposite treatment. The cognitive tasks consisted of the Delayed Non-Matching-to-Sample (DNMS), the Delayed Response (DR), and the Delayed Recognition Span Test (spatial-DRST). The emotional tasks included an object Approach-Avoidance task and a task in which monkeys were played videos of unfamiliar conspecifics in different emotional context (Social Playbacks). The fine motor task was the Lifesaver task that required monkeys to remove a Lifesaver candy from rods of different complexity.T manipulations did not significantly affect visual recognition memory, working memory, reference memory or fine motor function at any age. In the Approach-Avoidance task, older monkeys, but not younger monkeys, spent more time in proximity of novel objects in the high T condition relative to the low T condition. In both age groups, high T increased watching time of threatening social stimuli in the Social Playbacks. These results suggest that T affects some aspects of emotional processing but has no effect on fine motor function or cognition in young or older male macaques. It is possible that the duration of T treatment was not long enough to affect cognition or fine motor function or that T levels were too high to improve these outcomes. An alternative explanation for the discrepancies of our findings with some of the cognitive and emotional effects of T reported in rodents and humans may be the use of a chemical castration, which reduced circulating gonadotropins in addition to T. Further studies will investigate whether the luteinizing hormone LH mediates the effects of T on brain function in male primates.

Effects of Separate or Combined Neonatal Damage to the Orbital Frontal Cortex and the Inferior Convexity on Object Recognition in Monkeys.

Unlike adult damage, neonatal damage to the inferior prefrontal convexity (IC) in monkeys spares learning and performance on the delayed nonmatching-to-sample (DNMS) task ( Málková et al. 2000). We investigated whether this sparing was due to compensation by undamaged orbital frontal cortex (O), an area also critical for DNMS, by comparing combined IC and O damage (Neo-ICO) with damage to O alone (Neo-O). Group Neo-ICO was impaired on DNMS learning at 3 months and 2 years of age. In contrast, Group Neo-O was impaired at 3 months, but recovered this function by 2 years, compared with Neo-IC and controls (N). We propose that the intact IC assumed the function of learning the DNMS rule for Group Neo-O. The persistent impairment after Neo-ICO lesions suggests that whereas O may likely support the rule acquisition in the absence of IC, no compensatory mechanisms are available after the combined damage. For the memory of lists of items, all groups were impaired at 3 months. At 2 years, the performance of Groups N and Neo-IC dramatically improved, whereas that of groups with O damage (Neo-O and Neo-ICO) remained impaired, indicating a critical role for O in recognition memory that cannot be substituted by another area.

Improved learning and memory with theta-burst stimulation of the fornix in rat model of traumatic brain injury.

Learning and memory deficits are a source of considerable morbidity after traumatic brain injury (TBI). We investigated the effect of different patterns of hippocampal stimulation via a fornix electrode on cognitively demanding tasks after TBI. Male Sprague-Dawley rats underwent fluid-percussion injury and were compared with sham-operated rats. Electrodes were implanted into the fornix and hippocampus, and stimulation of the fornix produced robust evoked potentials in the hippocampus. A 60-s delayed non-match-to-sample (DNMS) swim T-maze was serially performed using four stimulation patterns: no stimulation (No Stim), low-frequency stimulation (LFS, 5 Hz), high-frequency stimulation (HFS, 130 Hz), and theta-burst stimulation (TBS, 200 Hz in 50 ms trains, five trains per second; 60 µA biphasic pulses). In a separate cohort of sham and injured animals, Morris water maze (MWM) was performed with or without TBS. In the DNMS swim T-maze, LFS and HFS did not significantly improve performance after TBI. However, there was a significant difference in performance between TBI + No Stim and TBI + TBS groups (P < 0.05) with no significant difference between Sham + No Stim and TBI + TBS. In the MWM, latency in the TBI + TBS group was significantly different from TBI + No Stim starting on day 2 (P < 0.05) and was not different from Sham + No Stim. The TBI + TBS group performed significantly more platform crossings in the probe trial (P < 0.01) and exhibited improved search strategy starting on day 3 (P < 0.05) compared with TBI + No Stim. Deficits in learning and memory after TBI are improved with TBS of the hippocampus. HFS and LFS do not appear to produce as great an effect as TBS.

Extraction and restoration of hippocampal spatial memories with non-linear dynamical modeling.

To build a cognitive prosthesis that can replace the memory function of the hippocampus, it is essential to model the input-output function of the damaged hippocampal region, so the prosthetic device can stimulate the downstream hippocampal region, e.g., CA1, with the output signal, e.g., CA1 spike trains, predicted from the ongoing input signal, e.g., CA3 spike trains, and the identified input-output function, e.g., CA3-CA1 model. In order for the downstream region to form appropriate long-term memories based on the restored output signal, furthermore, the output signal should contain sufficient information about the memories that the animal has formed. In this study, we verify this premise by applying regression and classification modelings of the spatio-temporal patterns of spike trains to the hippocampal CA3 and CA1 data recorded from rats performing a memory-dependent delayed non-match-to-sample (DNMS) task. The regression model is essentially the multiple-input, multiple-output (MIMO) non-linear dynamical model of spike train transformation. It predicts the output spike trains based on the input spike trains and thus restores the output signal. In addition, the classification model interprets the signal by relating the spatio-temporal patterns to the memory events. We have found that: (1) both hippocampal CA3 and CA1 spike trains contain sufficient information for predicting the locations of the sample responses (i.e., left and right memories) during the DNMS task; and more importantly (2) the CA1 spike trains predicted from the CA3 spike trains by the MIMO model also are sufficient for predicting the locations on a single-trial basis. These results show quantitatively that, with a moderate number of unitary recordings from the hippocampus, the MIMO non-linear dynamical model is able to extract and restore spatial memory information for the formation of long-term memories and thus can serve as the computational basis of the hippocampal memory prosthesis.

Neuronal responses to face-like and facial stimuli in the monkey superior colliculus

The superficial layers of the superior colliculus (sSC) appear to function as a subcortical visual pathway that bypasses the striate cortex for the rapid processing of coarse facial information. We investigated the responses of neurons in the monkey sSC during a delayed non-matching-to-sample (DNMS) task in which monkeys were required to discriminate among five categories of visual stimuli [photos of faces with different gaze directions, line drawings of faces, face-like patterns (three dark blobs on a bright oval), eye-like patterns, and simple geometric patterns]. Of the 605 sSC neurons recorded, 216 neurons responded to the visual stimuli. Among the stimuli, face-like patterns elicited responses with the shortest latencies. Low-pass filtering of the images did not influence the responses. However, scrambling of the images increased the responses in the late phase, and this was consistent with a feedback influence from upstream areas. A multidimensional scaling (MDS) analysis of the population data indicated that the sSC neurons could separately encode face-like patterns during the first 25-ms period after stimulus onset, and stimulus categorization developed in the next three 25-ms periods. The amount of stimulus information conveyed by the sSC neurons and the number of stimulus-differentiating neurons were consistently higher during the 2nd to 4th 25-ms periods than during the first 25-ms period. These results suggested that population activity of the sSC neurons preferentially filtered face-like patterns with short latencies to allow for the rapid processing of coarse facial information and developed categorization of the stimuli in later phases through feedback from upstream areas.

Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats

Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor. The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity. Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-fluorouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus. Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls. Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy.

Both PKMζ and KIBRA are closely related to reference memory but not working memory in a T-maze task in rats

Protein kinase M zeta (PKMζ) and the kidney and brain protein (KIBRA) play important roles in various forms of memories. However, whether they are involved in performing the T-maze task is still unknown. In this study, the delayed nonmatch-to-sample (DNMS) task in a T-maze was given to rats. The percentage of correct choices denoting the performance accuracy was calculated and the protein levels of PKMζ and KIBRA in rat's prefrontal cortex were measured. The results showed significantly increased performance accuracy after the training phase, which was maintained on the next day in groups with a delay of 10s but not 30s, indicating that 30s is too long for rats to maintain working memory. As for the expressions of PKMζ and KIBRA, significant increases were observed 1day after the training phase, indicating that the formation of reference memory accompanies an increase in PKMζ and KIBRA. No significant difference was found among groups with various delay intervals, indicating that the expressions of PKMζ and KIBRA exert no effects on the performance of working memory. These results provide the first evidence that KIBRA as well as PKMζ is closely related to reference memory but not working memory in rats.

Systemic and intra-rhinal-cortical 17-β estradiol administration modulate object-recognition memory in ovariectomized female rats

Previous studies using the novel-object-preference (NOP) test suggest that estrogen (E) replacement in ovariectomized rodents can lead to enhanced novelty preference. The present study aimed to determine: 1) whether the effect of E on NOP performance is the result of enhanced preference for novelty, per se, or facilitated object-recognition memory, and 2) whether E affects NOP performance through actions it has within the perirhinal cortex/entorhinal cortex region (PRh/EC). Ovariectomized rats received either systemic chronic low 17-β estradiol (E2; ~20pg/ml serum) replacement alone or in combination with systemic acute high administration of estradiol benzoate (EB; 10μg), or in combination with intracranial infusions of E2 (244.8pg/μl) or vehicle into the PRh/EC. For one of the intracranial experiments, E2 was infused either immediately before, immediately after, or 2h following the familiarization (i.e., learning) phase of the NOP test. In light of recent evidence that raises questions about the internal validity of the NOP test as a method of indexing object-recognition memory, we also tested rats on a delayed nonmatch-to-sample (DNMS) task of object recognition following systemic and intra-PRh/EC infusions of E2. Both systemic acute and intra-PRh/EC infusions of E enhanced novelty preference, but only when administered either before or immediately following familiarization. In contrast, high E (both systemic acute and intra-PRh/EC) impaired performance on the DNMS task. The findings suggest that while E2 in the PRh/EC can enhance novelty preference, this effect is probably not due to an improvement in object-recognition abilities.

Prefrontal-Temporal Disconnection Impairs Recognition Memory but Not Familiarity Discrimination

Neural mechanisms in the temporal lobe are essential for recognition memory. Evidence from human functional imaging and neuropsychology, and monkey neurophysiology and neuropsychology also suggests a role for prefrontal cortex in recognition memory. To examine the interaction of these cortical regions in support of recognition memory we tested rhesus monkeys with prefrontal-inferotemporal (PFC-IT) cortical disconnection on two recognition memory tasks, a "constant negative" task, and delayed nonmatching-to-sample (DNMS). In the constant negative task monkeys were presented with sets of 100 discrimination problems. In each problem one unrewarded object was presented once every day, and became familiar over the course of several days testing. The other, rewarded object was always novel. In this task monkeys learned to avoid the familiar constant negatives and choose the novel objects, so performance on this task is guided by a sense of familiarity for the constant negatives. Following PFC-IT disconnection monkeys were severely impaired at reacquiring the rule (to avoid familiar items) but were subsequently unimpaired at acquiring new constant negative problems, thus displaying intact familiarity recognition. The same monkeys were impaired in the acquisition of the DNMS task, as well as memory for lists of objects. This dissociation between two tests of recognition memory is best explained in terms of our general hypothesis that PFC-IT interactions support the representation of temporally complex events, which is necessary in DNMS but not in constant negative. These findings, furthermore, indicate that stimulus familiarity can be represented in temporal cortex without input from prefrontal cortex.

Design of optimal stimulation patterns for neuronal ensembles based on Volterra-type hierarchical modeling

This paper presents a general methodology for the optimal design of stimulation patterns applied to neuronal ensembles in order to elicit a desired effect. The methodology follows a variant of the hierarchical Volterra modeling approach that utilizes input–output data to construct predictive models that describe the effects of interactions among multiple input events in an ascending order of interaction complexity. The illustrative example presented in this paper concerns the multi-unit activity of CA1 neurons in the hippocampus of a rodent performing a learned delayed-nonmatch-to-sample (DNMS) task. The multi-unit activity of the hippocampal CA1 neurons is recorded via chronically implanted multi-electrode arrays during this task. The obtained model quantifies the likelihood of having correct performance of the specific task for a given multi-unit (spatiotemporal) activity pattern of a CA1 neuronal ensemble during the ‘sample presentation’ phase of the DNMS task. The model can be used to determine computationally (off-line) the ‘optimal’ multi-unit stimulation pattern that maximizes the likelihood of inducing the correct performance of the DNMS task. Our working hypothesis is that application of this optimal stimulation pattern will enhance performance of the DNMS task due to enhancement of memory formation and storage during the ‘sample presentation’ phase of the task.

Role of the Hippocampus in Memory Formation : Restorative Encoding Memory Integration Neural Device As a Cognitive Neural Prosthesis

Remind, which stands for "restorative encoding memory integration neural device," is a Defense Advanced Research Projects Agency (DARPA)-sponsored program to construct the first-ever cognitive prosthesis to replace lost memory function and enhance the existing memory capacity in animals and, ultimately, in humans. Reaching this goal involves understanding something fundamental about the brain that has not been understood previously: how the brain internally codes memories. In developing a hippocampal prosthesis for the rat, we have been able to demonstrate a multiple-input, multiple- output (MIMO) nonlinear model that predicts in real time the spatiotemporal codes for specific memories required for correct performance on a standard learning/memory task, i.e., delayed-nonmatch-to-sample (DNMS) memory. The MIMO model has been tested successfully in a number of contexts; most notably, in animals with a pharmacologically disabled hippocampus, we were able to reinstate long-term memories necessary for correct DNMS behavior by substituting a MIMO model-predicted code, delivered by electrical stimulation to the hippocampus through an array of electrodes, resulting in spatiotemporal hippocampal activity that is normally generated endogenously. We also have shown that delivering the same model-predicted code to electrode-implanted control animals with a normally functioning hippocampus substantially enhances animals memory capacity above control levels. These results in rodents have formed the basis for extending the MIMO model to nonhuman primates; this is now underway as the last step of the REMIND program before developing a MIMO-based cognitive prosthesis for humans.

A nonlinear model for hippocampal cognitive prosthesis: memory facilitation by hippocampal ensemble stimulation.

Collaborative investigations have characterized how multineuron hippocampal ensembles encode memory necessary for subsequent successful performance by rodents in a delayed nonmatch to sample (DNMS) task and utilized that information to provide the basis for a memory prosthesis to enhance performance. By employing a unique nonlinear dynamic multi-input/multi-output (MIMO) model, developed and adapted to hippocampal neural ensemble firing patterns derived from simultaneous recorded CA1 and CA3 activity, it was possible to extract information encoded in the sample phase necessary for successful performance in the nonmatch phase of the task. The extension of this MIMO model to online delivery of electrical stimulation delivered to the same recording loci that mimicked successful CA1 firing patterns, provided the means to increase levels of performance on a trial-by-trial basis. Inclusion of several control procedures provides evidence for the specificity of effective MIMO model generated patterns of electrical stimulation. Increased utility of the MIMO model as a prosthesis device was exhibited by the demonstration of cumulative increases in DNMS task performance with repeated MIMO stimulation over many sessions on both stimulation and nonstimulation trials, suggesting overall system modification with continued exposure. Results reported here are compatible with and extend prior demonstrations and further support the candidacy of the MIMO model as an effective cortical prosthesis.

A hippocampal cognitive prosthesis: multi-input, multi-output nonlinear modeling and VLSI implementation.

This paper describes the development of a cognitive prosthesis designed to restore the ability to form new long-term memories typically lost after damage to the hippocampus. The animal model used is delayed nonmatch-to-sample (DNMS) behavior in the rat, and the "core" of the prosthesis is a biomimetic multi-input/multi-output (MIMO) nonlinear model that provides the capability for predicting spatio-temporal spike train output of hippocampus (CA1) based on spatio-temporal spike train inputs recorded presynaptically to CA1 (e.g., CA3). We demonstrate the capability of the MIMO model for highly accurate predictions of CA1 coded memories that can be made on a single-trial basis and in real-time. When hippocampal CA1 function is blocked and long-term memory formation is lost, successful DNMS behavior also is abolished. However, when MIMO model predictions are used to reinstate CA1 memory-related activity by driving spatio-temporal electrical stimulation of hippocampal output to mimic the patterns of activity observed in control conditions, successful DNMS behavior is restored. We also outline the design in very-large-scale integration for a hardware implementation of a 16-input, 16-output MIMO model, along with spike sorting, amplification, and other functions necessary for a total system, when coupled together with electrode arrays to record extracellularly from populations of hippocampal neurons, that can serve as a cognitive prosthesis in behaving animals.

Short-term testosterone manipulations modulate visual recognition memory and some aspects of emotional reactivity in male rhesus monkeys

The role of testosterone (T) in modulating cognitive function and emotion in men remains unclear. The paucity of animal studies has likely contributed to the slow progress in this area. In particular, studies in nonhuman primates have been lacking. Our laboratory has begun to address this issue by pharmacologically manipulating T levels in intact male rhesus monkeys, using blind, placebo-controlled, crossover designs. We previously found that T-suppressed monkeys receiving supraphysiological T for 4weeks had lower visual recognition memory for long delays and enhanced attention to videos of negative social stimuli (Lacreuse et al., 2009, 2010) compared to when treated with oil. To further delineate the conditions under which T affects cognition and emotion, the present study focused on the short-term effects of physiological T. Six intact males were treated with the gonadotropin-releasing hormone antagonist degarelix (3mg/kg) for 7days and received one injection of T enanthate (5mg/kg) followed by one injection of oil vehicle 7days later (n=3), or the reverse treatment (n=3). Performance on two computerized tasks, the Delayed-non-matching-to-sample (DNMS) with random delays and the object-Delayed Recognition Span test (object-DRST) and one task of emotional reactivity, an approach/avoidance task of negative, familiar and novel objects, was examined at baseline and 3–5days after treatment. DNMS performance was significantly better when monkeys were treated with T compared to oil, independently of the delay duration or the nature (emotional or neutral) of the stimuli. Performance on the object-DRST was unaffected. Interestingly, subtle changes in emotional reactivity were also observed: T administration was associated with fewer object contacts, especially on negative objects, without overt changes in anxious behaviors. These results may reflect increased vigilance and alertness with high T. Altogether, the data suggest that changes in general arousal may underlie the beneficial effects of T on DNMS performance. This hypothesis will require further study with objective measures of physiological arousal.

Impairment in delayed nonmatching to sample following lesions of dorsal prefrontal cortex.

The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Nonmatching to Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore, Schettler, Killiany, Rosene, & Moss, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought.

Dentate gyrus granule cell firing patterns can induce mossy fiber long‐term potentiation in vitro

Hippocampal granule cells transmit information about behaviorally-relevant stimuli to CA3 pyramidal cells via mossy fiber synapses. These synapses express a form of long-term potentiation (mfLTP) that is non-Hebbian and does not require NMDA receptors. mfLTP is thought to be induced and expressed presynaptically, hence, the major determinant of whether mfLTP occurs is activity in the granule cells. However, it remains unclear whether mfLTP can be induced by activity patterns that granule cells exhibit in vivo, and-if so-what context generates these patterns. To address these issues, we examined granule cell activity from in vivo recordings from rats during performance of a delayed nonmatch-to-sample (DNMS) task and found that granule cells exhibit a wide range of spike patterns. In vitro slice experiments in mice demonstrated that some, but not all, of these patterns of activity could induce mfLTP. By further defining the activity thresholds for mfLTP in hippocampal slices, we found that mfLTP can only be induced by spike patterns that fire in high frequency bursts with a low average firing frequency. Using this information, we then screened for suprathreshold bursts of activity during the DNMS task. In a subset of cells, suprathreshold bursts occurred preferentially during the sampling phase of the task. If suprathreshold bursting took place later, during the delay phase, task performance was disrupted. We conclude that mfLTP can be induced by granule cell spike patterns during a memory task, and that the timing of mfLTP induction can predict task performance.

Memory encoding in hippocampal ensembles is negatively influenced by cannabinoid CB1 receptors

It has previously been demonstrated that the detrimental effect on the performance of a delayed nonmatch to sample (DNMS) memory task by exogenously administered cannabinoid (CB1) receptor agonist, WIN 55212-2 (WIN), is reversed by the receptor antagonist rimonabant. In addition, rimonabant administered alone elevates DNMS performance, presumably through the suppression of negative modulation by released endocannabinoids during normal task performance. Other investigations have shown that rimonabant enhances encoding of DNMS task-relevant information on a trial-by-trial, delay-dependent basis. In this study, these reciprocal pharmacological actions were completely characterized by long-term, chronic intrahippocampal infusion of both agents (WIN and rimonabant) in successive 2-week intervals. Such long-term exposure allowed extraction and confirmation of task-related firing patterns, in which rimonabant reversed the effects of CB1 agonists. This information was then utilized to artificially impose the facilitatory effects of rimonabant and to reverse the effects of WIN on DNMS performance, by delivering multichannel electrical stimulation in the same firing patterns to the same hippocampal regions. Direct comparison of normal and WIN-injected subjects, in which rimonabant injections and ensemble firing facilitated performance, verified reversal of the modulation of hippocampal memory processes by CB1 receptor agonists, including released endocannabinoids.

Tracking the changes of hippocampal population nonlinear dynamics in rats learning a memory-dependent task.

Neurobiological processes associated with learning are known to be highly nonlinear, dynamical, and time-varying. Characterizing the time-varying functional input-output properties of neural systems is a critical step to understand the neurobiological basis of learning. In this paper, we present a study on tracking of the changes of neural dynamics in rat hippocampus during learning of a memory-dependent delayed nonmatch-to-sample (DNMS) task. The rats were first trained to perform the DNMS task without a delay between the sample and response events. After reaching a performance level, they were subjected to the DNMS task with variable delays with a 5s mean duration. Spike trains were recorded from hippocampal CA3 (input) and CA1 (output) regions during all training sessions and constitute the input-output data for modeling. We applied the time-varying Generalized Laguerre-Volterra Model to study the changes of the CA3-CA1 nonlinear dynamics using these data. Result showed significant changes in the Volterra kernels after the introduction of delays. This result suggests that the CA3-CA1 nonlinear dynamics established in the initial training sessions underwent a functional reorganization as animals were learning to perform the task that now requires delays.