Hippocampal Place Fields Maintain a Coherent and Flexible Map across Long Timescales.

To provide a substrate for remembering where in space events have occurred, place cells must reliably encode the same positions across long timescales. However, in many cases, place cells exhibit instability by randomly reorganizing their place fields between experiences, challenging this premise. Recent evidence suggests that, in some cases, instability could also arise from coherent rotations of place fields, as well as from random reorganization. To investigate this possibility, we performed in vivo calcium imaging in dorsal hippocampal region CA1 of freely moving mice while they explored two arenas with different geometry and visual cues across 8 days. The two arenas were rotated randomly between sessions and then connected, allowing us to probe how cue rotations, the integration of new information about the environment, and the passage of time concurrently influenced the spatial coherence of place fields. We found that spatially coherent rotations of place-field maps in the same arena predominated, persisting up to 6 days later, and that they frequently rotated in a manner that did not match that of the arena rotation. Furthermore, place-field maps were flexible, as mice frequently employed a similar, coherent configuration of place fields to represent each arena despite their differing geometry and eventual connection. These results highlight the ability of the hippocampus to retain consistent relationships between cells across long timescales and suggest that, in many cases, apparent instability might result from a coherent rotation of place fields.

Characterizing context-dependent differential firing activity in the hippocampus and entorhinal cortex.

The rat hippocampus and entorhinal cortex have been shown to possess neurons with place fields that modulate their firing properties under different behavioral contexts. Such context-dependent changes in neural activity are commonly studied through electrophysiological experiments in which a rat performs a continuous spatial alternation task on a T-maze. Previous research has analyzed context-based differential firing during this task by describing differences in the mean firing activity between left-turn and right-turn experimental trials. In this article, we develop qualitative and quantitative methods to characterize and compare changes in trial-to-trial firing rate variability for sets of experimental contexts. We apply these methods to cells in the CA1 region of hippocampus and in the dorsocaudal medial entorhinal cortex (dcMEC), characterizing the context-dependent differences in spiking activity during spatial alternation. We identify a subset of cells with context-dependent changes in firing rate variability. Additionally, we show that dcMEC populations encode turn direction uniformly throughout the T-maze stem, whereas CA1 populations encode context at major waypoints in the spatial trajectory. Our results suggest scenarios in which individual cells that sparsely provide information on turn direction might combine in the aggregate to produce a robust population encoding.

Influence of cocaine self-administration on learning related to prefrontal cortex or hippocampus functioning in rats.

RATIONALE: Individuals who abuse cocaine have cognitive deficits, particularly in functions associated with the orbitofrontal cortex. It is not clear to what extent the impact of cocaine on cognitive functioning is related to its role as a behavioral reinforcer. A preclinical means to investigate this issue is to use a yoked-triad procedure in which sets of three animals either contingently self-administer cocaine or receive passive administration of cocaine or saline in a noncontingent manner. OBJECTIVE: Using this procedure, we assessed cocaine's effect on learning that requires a functionally intact prefrontal cortex (prelimbic or insular/orbital subregions) or hippocampus. METHODS: Rats self-administering 1-mg/kg unit doses of cocaine responded under a fixed-ratio 5, time-out 20-s schedule of drug delivery. Testing took place in a radial-arm maze within the first 30 min after 2-hr drug sessions ended, beginning after 2.5 months of cocaine or saline exposure. RESULTS: Rats self-administering cocaine earned 14-18 infusions on average throughout different phases of the study. In groupwise comparisons, learning in the visually guided delayed win-shift (prelimbic prefrontal cortex-related) and win-shift (hippocampus-related) tasks was not influenced by contingent or noncontingent cocaine exposure. Session latency, though, was shorter in both cocaine-exposed groups during the win-shift task. During the odor-guided delayed win-shift task (insular/orbital prefrontal cortex-related), learning was disrupted in rats self-administering cocaine, with no influence of noncontingent cocaine exposure. CONCLUSIONS: Based on these and previous findings, learning related to functioning of the insular/orbital prefrontal cortex and amygdala is the most consistently disrupted in cocaine-intoxicated rats after long-term drug exposure.

Complementary tasks to measure working memory in distinct prefrontal cortex subregions in rats.

Acquisition of odor-guided or visually-guided delayed win-shift behavior was evaluated in rats after lidocaine-induced inactivation within the agranular insular area of the prefrontal cortex (PFC) or the prelimbic area of the PFC. Additional sites and tasks were used to control for neuroanatomical and behavioral specificity of lidocaine inactivation of the agranular insular and prelimbic areas. Results showed that acquisition of the odor-guided delayed win-shift task was dependent on the agranular insular area, whereas acquisition of the visually-guided version was dependent on the prelimbic area. This dissociation suggests that the stimulus modality used is critical for revealing working memory functions of different PFC subregions. The described methods provide a complementary means to study working memory in PFC subregions using a radial-arm maze.

Oscillatory entrainment of striatal neurons in freely moving rats.

Oscillations and synchrony in basal ganglia circuits may play a key role in the organization of voluntary actions and habits. We recorded single units and local field potentials from multiple striatal and cortical locations simultaneously, over a range of behavioral states. We observed opposite gradients of oscillatory entrainment, with dorsal/lateral striatal neurons entrained to high-voltage spindle oscillations ("spike wave discharges") and ventral/medial striatal neurons entrained to the hippocampal theta rhythm. While the majority of units were likely medium-spiny projection neurons, a second neuronal population showed characteristic features of fast-spiking GABAergic interneurons, including tonic activity, brief waveforms, and high-frequency bursts. These fired at an earlier spindle phase than the main neuronal population, and their density within striatum corresponded closely to the intensity of spindle oscillations. The orchestration of oscillatory activity by networks of striatal interneurons may be an important mechanism in the pathophysiology of neurological disorders such as Parkinson's disease.

Hippocampal memory system function and the regulation of cocaine self-administration behavior in rats.

There is considerable interest in elucidating neurocognitive mechanisms of cocaine addiction. This report focuses on the hippocampal memory system. Using food reward, two cognitive tasks were examined after lidocaine inactivation of the dorsal (dSUB) or ventral (vSUB) subiculum, the primary hippocampal output regions in rats. These tasks were conducted to first identify functionally relevant stereotaxic coordinates within the hippocampal memory system, in order to then examine its role in regulating drug-seeking and drug-taking behavior studied under a contextually discriminable FI 5-min(FR5:S) second-order schedule of cocaine and brief stimulus delivery. Inactivation of the dSUB and vSUB with 10microg lidocaine impaired hippocampal-dependent win-shift performance. Amygdalar-dependant conditioned cue preference, used as a test for behavioral specificity of lidocaine, was not affected following inactivation of either site. Inactivation of the dSUB with 100 microg lidocaine significantly reduced drug-seeking and drug-taking behavior studied during the cocaine self-administration maintenance phase. Following extinction, inactivation of neither the dSUB nor vSUB influenced reinstatement of drug-seeking behavior induced by drug-paired cues presented alone or with a cocaine priming injection. The impairments in win-shift performance are consistent with the spatial processing functions of the dSUB and vSUB, and the reduction in drug-taking behavior is consistent with the non-spatial temporal processing functions of the dSUB. The lack of an effect of dSUB and vSUB inactivation on reinstatement of drug-seeking behavior may relate to the fact that the contextual associations with cocaine were well-practiced at the time of cue reinstatement testing, and therefore, drug-seeking behavior was likely regulated by nonhippocampal-dependent mechanisms.

Effects of persistent cocaine self-administration on amygdala-dependent and dorsal striatum-dependent learning in rats.

RATIONALE: The influence of persistent cocaine self-administration on learning and memory has never been evaluated. OBJECTIVES: Our objective was to isolate the effects of contingently administered cocaine from those of its general pharmacological or non-contingent actions on multiple memory system functioning. METHODS: A triad design was used to yoke passive cocaine and saline administration to the behavior of rats who were actively self-administering cocaine. Following 4 weeks of cocaine or saline exposure in 2-h sessions, six triads were tested in the amygdala-dependent conditioned cue preference task and dorsal striatum-dependent win-stay task in an eight-arm radial maze environment. Drug or saline sessions continued throughout task testing. RESULTS: Throughout task testing, rats actively and passively exposed to cocaine sustained a total daily intake of approximately 15 mg/kg. During the conditioned cue preference task, saline-exposed rats showed robust conditioned preference for a Froot Loops-paired cue. Rats actively and passively exposed to cocaine showed no evidence of conditioning despite normal exploration in the maze during preference testing. For the win-stay task, no significant differences were found among the three groups in terms of the number of sessions to acquire the task or task accuracy at criterion. Rats actively or passively exposed to cocaine, however, completed sessions more quickly than saline-exposed rats at criterion. CONCLUSION: These findings suggest that contingent and non-contingent cocaine administration similarly disrupt stimulus-reward functions of the amygdala, but do not disrupt stimulus-response functions of the dorsal striatum. This dissociation may relate to differences in the rate by which dopamine is cleared from these tissues following cocaine exposure or possibly to cocaine-induced devaluation of natural rewards, which influences stimulus-reward learning, but not stimulus-response learning.

Stimulus-response functions of the lateral dorsal striatum and regulation of behavior studied in a cocaine maintenance/cue reinstatement model in rats.

RATIONALE: To investigate potential neurocognitive mechanisms underlying drug-seeking and drug-taking behavior, the effects of reversible lidocaine-induced inactivation of the lateral dorsal striatum (DST) on behavior studied in a drug maintenance/cue reinstatement model were evaluated. This region of the DST was investigated because it selectively regulates stimulus-response learning that is disrupted by 10 microg of bilaterally infused lidocaine. METHODS: Rats ( n=6) were trained to self-administer 1 mg/kg per infusion cocaine under a second-order schedule of drug delivery. The effects of bilateral lidocaine (30-100 microg) inactivation of the lateral DST were evaluated during drug maintenance tests as well as during tests in which responding was reinstated by cocaine-associated cues presented in combination with a cocaine priming injection. The lower 10 microg dose was used to examine the effects of lidocaine on reinstatement of responding induced by presentation of cues alone. RESULTS: During drug maintenance tests, drug-seeking behavior was significantly increased after inactivation by 100 microg lidocaine. The number of infusions earned did not change. During cue-induced reinstatement tests preceded by a cocaine priming injection, 100 microg lidocaine significantly decreased both drug-seeking behavior and the number of infusion-paired light deliveries earned. During reinstatement tests with cues presented alone, inactivation of the lateral DST by 10 microg lidocaine did not influence either behavior. CONCLUSIONS: These findings suggest that stimulus-response functions of the lateral DST may regulate the dose-related effects of self-administered cocaine because the lidocaine-induced changes in behavior during the maintenance and cocaine priming tests resembled the effects of exposure to increasingly lower doses of cocaine, respectively. Given the lack of an effect of lidocaine during the cues-alone tests, the lateral DST does not appear to regulate drug-seeking behavior per se (i.e., responding maintained by drug-associated cues at times when drug is not available).

Critical role of the hippocampus in memory for sequences of events.

Recent models of hippocampal function emphasize the potential role of this brain structure in encoding and retrieving sequences of events that compose episodic memories. Here we show that hippocampal lesions produce a severe and selective impairment in the capacity of rats to remember the sequential ordering of a series of odors, despite an intact capacity to recognize odors that recently occurred. These findings support the hypothesis that hippocampal networks mediate associations between sequential events that constitute elements of an episodic memory.

Dissociable effects of lidocaine inactivation of the rostral and caudal basolateral amygdala on the maintenance and reinstatement of cocaine-seeking behavior in rats.

Cocaine addiction is a chronically relapsing brain disease, but its neural basis is not yet well understood. Clinical reports underscore the possible importance of associative processes for regulating at least some aspects of cocaine addiction. The present study reports the effects of reversible lidocaine-induced inactivation of rostral basolateral amygdala (rBLA) and caudal basolateral amygdala (cBLA) regions on the maintenance and reinstatement of drug-seeking behavior in rats trained to self-administer 1 mg/kg cocaine under a second order schedule of drug delivery. Both regions of the basolateral amygdala were investigated because they have dissociable effects on cognitive task performance. Results demonstrated that after self-administration training and a period of extinction and abstinence, lidocaine inactivation of the rBLA and cBLA attenuated the reinstatement of drug-seeking behavior induced by cocaine-associated cues examined in conjunction with a single priming injection of cocaine. In contrast, lidocaine inactivation of only the rBLA blocked reinstatement of drug-seeking behavior induced by cocaine-associated cues examined alone. Additional differences were shown during cocaine maintenance testing where inactivation of only the cBLA attenuated drug-seeking behavior. Drug intake was not altered. Thus, the rBLA and cBLA appear to selectively and dissociably regulate drug-seeking behavior under conditions of cocaine abstinence (cue-induced reinstatement) and repeated cocaine use (maintenance), respectively. These findings suggest that the basolateral amygdala may be more functionally heterogeneous than commonly thought for regulating drug-seeking behavior. The basis for this dissociation might be related to neuroanatomical connections of the rBLA and cBLA with segregated, but parallel, corticostriatalpallidothalamic circuits.