Egocentric boundary vector tuning of the retrosplenial cortex.

The retrosplenial cortex is reciprocally connected with multiple structures implicated in spatial cognition, and damage to the region itself produces numerous spatial impairments. Here, we sought to characterize spatial correlates of neurons within the region during free exploration in two-dimensional environments. We report that a large percentage of retrosplenial cortex neurons have spatial receptive fields that are active when environmental boundaries are positioned at a specific orientation and distance relative to the animal itself. We demonstrate that this vector-based location signal is encoded in egocentric coordinates, is localized to the dysgranular retrosplenial subregion, is independent of self-motion, and is context invariant. Further, we identify a subpopulation of neurons with this response property that are synchronized with the hippocampal theta oscillation. Accordingly, the current work identifies a robust egocentric spatial code in retrosplenial cortex that can facilitate spatial coordinate system transformations and support the anchoring, generation, and utilization of allocentric representations.

Neuronal representation of environmental boundaries in egocentric coordinates.

Movement through space is a fundamental behavior for all animals. Cognitive maps of environments are encoded in the hippocampal formation in an allocentric reference frame, but motor movements that comprise physical navigation are represented within an egocentric reference frame. Allocentric navigational plans must be converted to an egocentric reference frame prior to implementation as overt behavior. Here we describe an egocentric spatial representation of environmental boundaries in the dorsomedial striatum.

Neural mechanisms of navigation involving interactions of cortical and subcortical structures.

Animals must perform spatial navigation for a range of different behaviors, including selection of trajectories toward goal locations and foraging for food sources. To serve this function, a number of different brain regions play a role in coding different dimensions of sensory input important for spatial behavior, including the entorhinal cortex, the retrosplenial cortex, the hippocampus, and the medial septum. This article will review data concerning the coding of the spatial aspects of animal behavior, including location of the animal within an environment, the speed of movement, the trajectory of movement, the direction of the head in the environment, and the position of barriers and objects both relative to the animal's head direction (egocentric) and relative to the layout of the environment (allocentric). The mechanisms for coding these important spatial representations are not yet fully understood but could involve mechanisms including integration of self-motion information or coding of location based on the angle of sensory features in the environment. We will review available data and theories about the mechanisms for coding of spatial representations. The computation of different aspects of spatial representation from available sensory input requires complex cortical processing mechanisms for transformation from egocentric to allocentric coordinates that will only be understood through a combination of neurophysiological studies and computational modeling.

Models of spatial and temporal dimensions of memory.

Episodic memory involves coding of the spatial location and time of individual events. Coding of space and time is also relevant to working memory, spatial navigation, and the disambiguation of overlapping memory representations. Neurophysiological data demonstrate that neuronal activity codes the current, past and future location of an animal as well as temporal intervals within a task. Models have addressed how neural coding of space and time for memory function could arise, with both dimensions coded by the same neurons. Neural coding could depend upon network oscillatory and attractor dynamics as well as modulation of neuronal intrinsic properties. These models are relevant to the coding of space and time involving structures including the hippocampus, entorhinal cortex, retrosplenial cortex, striatum and parahippocampal gyrus, which have been implicated in both animal and human studies.

Potential roles of cholinergic modulation in the neural coding of location and movement speed.

Behavioral data suggest that cholinergic modulation may play a role in certain aspects of spatial memory, and neurophysiological data demonstrate neurons that fire in response to spatial dimensions, including grid cells and place cells that respond on the basis of location and running speed. These neurons show firing responses that depend upon the visual configuration of the environment, due to coding in visually-responsive regions of the neocortex. This review focuses on the physiological effects of acetylcholine that may influence the sensory coding of spatial dimensions relevant to behavior. In particular, the local circuit effects of acetylcholine within the cortex regulate the influence of sensory input relative to internal memory representations via presynaptic inhibition of excitatory and inhibitory synaptic transmission, and the modulation of intrinsic currents in cortical excitatory and inhibitory neurons. In addition, circuit effects of acetylcholine regulate the dynamics of cortical circuits including oscillations at theta and gamma frequencies. These effects of acetylcholine on local circuits and network dynamics could underlie the role of acetylcholine in coding of spatial information for the performance of spatial memory tasks.

Multiple Running Speed Signals in Medial Entorhinal Cortex.

Grid cells in medial entorhinal cortex (MEC) can be modeled using oscillatory interference or attractor dynamic mechanisms that perform path integration, a computation requiring information about running direction and speed. The two classes of computational models often use either an oscillatory frequency or a firing rate that increases as a function of running speed. Yet it is currently not known whether these are two manifestations of the same speed signal or dissociable signals with potentially different anatomical substrates. We examined coding of running speed in MEC and identified these two speed signals to be independent of each other within individual neurons. The medial septum (MS) is strongly linked to locomotor behavior, and removal of MS input resulted in strengthening of the firing rate speed signal, while decreasing the strength of the oscillatory speed signal. Thus, two speed signals are present in MEC that are differentially affected by disrupted MS input.

Modelling effects on grid cells of sensory input during self-motion.

The neural coding of spatial location for memory function may involve grid cells in the medial entorhinal cortex, but the mechanism of generating the spatial responses of grid cells remains unclear. This review describes some current theories and experimental data concerning the role of sensory input in generating the regular spatial firing patterns of grid cells, and changes in grid cell firing fields with movement of environmental barriers. As described here, the influence of visual features on spatial firing could involve either computations of self-motion based on optic flow, or computations of absolute position based on the angle and distance of static visual cues. Due to anatomical selectivity of retinotopic processing, the sensory features on the walls of an environment may have a stronger effect on ventral grid cells that have wider spaced firing fields, whereas the sensory features on the ground plane may influence the firing of dorsal grid cells with narrower spacing between firing fields. These sensory influences could contribute to the potential functional role of grid cells in guiding goal-directed navigation.

Age-related decrease in theta and gamma coherence across dorsal ca1 pyramidale and radiatum layers.

In both humans and rodents, aging is linked to impairments in hippocampus dependent learning. Given such deficits, one would expect corresponding changes in hippocampal local field potentials, which represent the integration of multiple inputs onto a given dendritic field within the hippocampus. The current experiment examined coherence of theta and gamma in young and aged rats at sub-millimeter and millimeter distant locations both within and across layers in CA1 of the dorsal hippocampus. The degree to which different dendritic layers show coherent oscillations indicates the uniformity of the inputs and local circuitry, and may form an important element for processing information. Aged rats had lower coherence in all frequency ranges; this was most marked within a layer as the distance between electrodes increased. Notably, unlike younger rats, in the aged rats coherence was not affected by running on the maze. Furthermore, despite the previously reported effects of cholinergic activation on theta frequency and power, there was no effect of the cholinomimetic physostigmine on coherence. These data indicate an age related fragmentation in hippocampal processing that may underlie some of the observed learning and memory deficits.

Theta dynamics in rat: speed and acceleration across the Septotemporal axis.

Theta (6-12 Hz) rhythmicity in the local field potential (LFP) reflects a clocking mechanism that brings physically isolated neurons together in time, allowing for the integration and segregation of distributed cell assemblies. Variation in the theta signal has been linked to locomotor speed, sensorimotor integration as well as cognitive processing. Previously, we have characterized the relationship between locomotor speed and theta power and how that relationship varies across the septotemporal (long) axis of the hippocampus (HPC). The current study investigated the relationship between whole body acceleration, deceleration and theta indices at CA1 and dentate gyrus (DG) sites along the septotemporal axis of the HPC in rats. Results indicate that whole body acceleration and deceleration predicts a significant amount of variability in the theta signal beyond variation in locomotor speed. Furthermore, deceleration was more predictive of variation in theta amplitude as compared to acceleration as rats traversed a linear track. Such findings highlight key variables that systematically predict the variability in the theta signal across the long axis of the HPC. A better understanding of the relative contribution of these quantifiable variables and their variation as a function of experience and environmental conditions should facilitate our understanding of the relationship between theta and sensorimotor/cognitive functions.

Novel acoustic stimuli can alter locomotor speed to hippocampal theta relationship.

Hippocampal theta (6-12 Hz) plays a critical role in synchronizing the discharge of action potentials, ultimately orchestrating individual neurons into large-scale ensembles. Alterations in theta dynamics may reflect variations in sensorimotor integration, the flow of sensory input, and/or cognitive processing. Previously we have investigated septotemporal variation in the locomotor speed to theta amplitude relationship as well as how that relationship is systematically altered as a function of novel, physical space. In the present study, we ask, beyond physical space, whether persistent and passive sound delivery can alter septal theta local field potential rhythm dynamics. Results indicate pronounced alterations in the slope of the speed to theta amplitude relationship as a function of sound presentation and location. Further, this reduction in slope habituates across days. The current findings highlight that moment-to-moment alterations in theta amplitude is a rich dynamic index that is quantitatively related to both alterations in motor behavior and sensory experience. The implications of these phenomena are discussed with respect to emergent cognitive functions subserved by hippocampal circuits.

Novel space alters theta and gamma synchrony across the longitudinal axis of the hippocampus.

Hippocampal theta (6-10 Hz) and gamma (25-50 Hz and 65-100 Hz) local field potentials (LFPs) reflect the dynamic synchronization evoked by inputs impinging upon hippocampal neurons. Novel experience is known to engage hippocampal physiology and promote successful encoding. Does novelty synchronize or desynchronize theta and/or gamma frequency inputs across the septotemporal (long) axis of the hippocampus (HPC)? The present study tested the hypothesis that a novel spatial environment would alter theta power and coherence across the long axis. We compared theta and gamma LFP signals at individual (power) and millimeter distant electrode pairs (coherence) within the dentate gyrus (DG) and CA1 region while rats navigated a runway (1) in a familiar environment, (2) with a modified path in the same environment and (3) in a novel space. Locomotion in novel space was related to increases in theta and gamma power at most CA1 and DG sites. The increase in theta and gamma power was concurrent with an increase in theta and gamma coherence across the long axis of CA1; however, there was a significant decrease in theta coherence across the long axis of the DG. These findings illustrate significant shifts in the synchrony of entorhinal, CA3 and/or neuromodulatory afferents conveying novel spatial information to the dendritic fields of CA1 and DG targets across the long axis of the HPC. This shift suggests that the entire theta/gamma-related input to the CA1 network, and likely output, receives and conveys a more coherent message in response to novel sensory experience. Such may contribute to the successful encoding of novel sensory experience.

Dissociation between dorsal and ventral hippocampal theta oscillations during decision-making.

Hippocampal theta oscillations are postulated to support mnemonic processes in humans and rodents. Theta oscillations facilitate encoding and spatial navigation, but to date, it has been difficult to dissociate the effects of volitional movement from the cognitive demands of a task. Therefore, we examined whether volitional movement or cognitive demands exerted a greater modulating factor over theta oscillations during decision-making. Given the anatomical, electrophysiological, and functional dissociations along the dorsal-ventral axis, theta oscillations were simultaneously recorded in the dorsal and ventral hippocampus in rats trained to switch between place and motor-response strategies. Stark differences in theta characteristics were found between the dorsal and ventral hippocampus in frequency, power, and coherence. Theta power increased in the dorsal, but decreased in the ventral hippocampus, during the decision-making epoch. Interestingly, the relationship between running speed and theta power was uncoupled during the decision-making epoch, a phenomenon limited to the dorsal hippocampus. Theta frequency increased in both the dorsal and ventral hippocampus during the decision epoch, although this effect was greater in the dorsal hippocampus. Despite these differences, ventral hippocampal theta was responsive to the navigation task; theta frequency, power, and coherence were all affected by cognitive demands. Theta coherence increased within the dorsal hippocampus during the decision-making epoch on all three tasks. However, coherence selectively increased throughout the hippocampus (dorsal to ventral) on the task with new hippocampal learning. Interestingly, most results were consistent across tasks, regardless of hippocampal-dependent learning. These data indicate increased integration and cooperation throughout the hippocampus during information processing.

Hippocampal theta, gamma, and theta-gamma coupling: effects of aging, environmental change, and cholinergic activation.

Hippocampal theta and gamma oscillations coordinate the timing of multiple inputs to hippocampal neurons and have been linked to information processing and the dynamics of encoding and retrieval. One major influence on hippocampal rhythmicity is from cholinergic afferents. In both humans and rodents, aging is linked to impairments in hippocampus-dependent function along with degradation of cholinergic function. Cholinomimetics can reverse some age-related memory impairments and modulate oscillations in the hippocampus. Therefore, one would expect corresponding changes in these oscillations and possible rescue with the cholinomimetic physostigmine. Hippocampal activity was recorded while animals explored a familiar or a novel maze configuration. Reexposure to a familiar situation resulted in minimal aging effects or changes in theta or gamma oscillations. In contrast, exploration of a novel maze configuration increased theta power; this was greater in adult than old animals, although the deficit was reversed with physostigmine. In contrast to the theta results, the effects of novelty, age, and/or physostigmine on gamma were relatively weak. Unrelated to the behavioral situation were an age-related decrease in the degree of theta-gamma coupling and the fact that physostigmine lowered the frequency of theta in both adult and old animals. The results indicate that age-related changes in gamma and theta modulation of gamma, while reflecting aging changes in hippocampal circuitry, seem less related to aging changes in information processing. In contrast, the data support a role for theta and the cholinergic system in encoding and that hippocampal aging is related to impaired encoding of new information.

Ketamine disrupts theta synchrony across the septotemporal axis of the CA1 region of hippocampus.

The hippocampal theta signal reflects moment-to-moment variation in the synchrony of synaptic input to hippocampal neurons. Consistent with the topography of hippocampal afferents, the synchrony (coherence) of the theta signal varies across the septotemporal axis. Septotemporal variation in the theta signal can also be observed in relation to ongoing and past experience. Thus there is a systematic decrease in the relationship between locomotor speed and theta power across the septotemporal axis, septal hippocampus exhibiting the strongest relationship. Conversely, theta in temporal hippocampus decrements over repeated behavioral experience (running episodes), while theta in the septal hippocampus does not. Ketamine is an N-methyl-D-aspartate (NMDA) antagonist that can decrease theta power. The present study examined whether ketamine treatment could alter theta coherence across the long axis independent of changes in locomotor behavior. Rats were well trained to navigate a linear runway and outfitted with electrodes at different septotemporal positions within CA1. Locomotor behavior and theta coherence and power were examined after administration of 2.5 and 10 mg/kg ketamine. Ketamine (2.5 mg/kg) decreased theta coherence between distant CA1 electrode sites without altering running speed or theta power. Both doses of ketamine also blunted and reversed the decrement in theta power observed at midseptotemporal and temporal electrodes over repeated run sessions. The results demonstrate the sensitivity of global network synchronization to relatively low doses of ketamine and septotemporal differences in the influence of ketamine on hippocampal dynamics in relation to past experience.

Theta and gamma coherence across the septotemporal axis during distinct behavioral states.

Theta (4-12 Hz) and gamma (40-100 Hz) field potentials represent the interaction of synchronized synaptic input onto distinct neuronal populations within the hippocampal formation. Theta is quite prominent during exploratory activity, locomotion, and REM sleep. Although it is generally acknowledged that theta is coherent throughout most of the hippocampus, there is significant variability in theta, as well as gamma, coherence across lamina at any particular septotemporal level of the hippocampus. Larger differences in theta coherence are observed across the septotemporal (long) axis. We have reported that during REM sleep there is a decrease in theta coherence across the long axis that varies with the topography of CA3/mossy cell input rather than the topography of the prominent entorhinal input. On the basis of differences in the rat's behavior as well as the activity of neuromodulatory inputs (e.g., noradrenergic and serotonergic), we hypothesized that theta coherence across the long axis would be greater during locomotion than REM sleep and exhibit a pattern more consistent with the topography of entorhinal inputs. We examined theta and gamma coherence indices at different septotemporal and laminar sites during distinct theta states: locomotion during maze running, REM sleep, following acute treatment with a θ-inducing cholinomimetic (physostigmine) and for comparison during slow-wave sleep. The results demonstrate a generally consistent pattern of theta and gamma coherence across the septotemporal axis of the hippocampus that is quite indifferent to sensory input and overt behavior. These results are discussed with regards to the neurobiological mechanisms that generate theta and gamma and the growing body of evidence linking theta and gamma indices to memory and other cognitive functions.

Pharmacological and physiological characterization of the tremulous jaw movement model of parkinsonian tremor: potential insights into the pathophysiology of tremor.

Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3-7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A(2A) antagonists). TJMs occur in the same 3-7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1-2 Hz), and postural tremor (8-14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor.

Septotemporal variation in dynamics of theta: speed and habituation.

Theta (6-12 Hz) field potentials and the synchronization (coherence) of these potentials present neural network indices of hippocampal physiology. Theta signals within the hippocampal formation may reflect alterations in sensorimotor integration, the flow of sensory input, and/or distinct cognitive operations. While the power and coherence of theta signals vary across lamina within the septal hippocampus, limited information is available about variation in these indices across the septotemporal (long) or areal axis. The present study examined the relationship of locomotor speed to theta indices at CA1 and dentate gyrus (DG) sites across the septotemporal axis as well as in the entorhinal cortex. Our findings demonstrate the dominant relationship of speed to theta indices at septal sites. This relationship diminished systematically with distance from the septal pole of the hippocampus at both CA1 and DG sites. While theta power at entorhinal sites varied in relation to speed, there were no differences across the areal axis of the entorhinal cortex. Locomotor speed was also related to changes in theta coherence along the septotemporal axis as well as between the hippocampus and entorhinal cortex. In addition to the speed-related variation, we observed a decrease in theta power at more temporal hippocampal sites over repeated behavioral testing within a single day that was not observed at septal sites. The results outline a dynamic and distributed pattern of network activity across the septotemporal axis of the hippocampus in relation to locomotor speed and recent past experience.

Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine. While the adenosine A(2A) antagonist MSX-3 was incapable of reversing the tremulous jaw movements induced by the 4.0mg/kg dose of pilocarpine, both MSX-3 and the adenosine A(2A) antagonist SCH58261 reversed the tremulous jaw movements elicited by 0.5mg/kg pilocarpine. Systemic administration of the adenosine A(1) antagonist DPCPX failed to reverse the tremulous jaw movements induced by either an acute 0.5mg/kg dose of the cholinomimetic pilocarpine or the DA D2 antagonist pimozide, indicating that the tremorolytic effects of adenosine antagonists may be receptor subtype specific. Behaviorally active doses of MSX-3 and SCH 58261 showed substantial in vivo occupancy of A(2A) receptors, but DPCPX did not. The results of these studies support the use of adenosine A(2A) antagonists for the treatment of tremor.

Theta and gamma coherence along the septotemporal axis of the hippocampus.

Theta and gamma rhythms synchronize neurons within and across brain structures. Both rhythms are widespread within the hippocampus during exploratory behavior and rapid-eye-movement (REM) sleep. How synchronous are these rhythms throughout the hippocampus? The present study examined theta and gamma coherence along the septotemporal (long) axis of the hippocampus in rats during REM sleep, a behavioral state during which theta signals are unaffected by external sensory input or ongoing behavior. Unilateral entorhinal cortical inputs are thought to play a prominent role in the current generation of theta, whereas current generation of gamma is primarily due to local GABAergic neurons. The septal 50% (4-5 mm) of the dentate gyrus (DG) receives a highly divergent, unilateral projection from any focal point along a lateral band of entorhinal neurons near the rhinal sulcus. We hypothesized that theta coherence in the target zone (septal DG) of this divergent entorhinal input would not vary, while gamma coherence would significantly decline with distance in this zone. However, both theta and gamma coherence decreased significantly along the long axis in the septal 50% of the hippocampus across both DG and CA1 electrode sites. In contrast, theta coherence between homotypic (e.g., DG to DG) sites in the contralateral hemisphere ( approximately 3-5 mm distant) were quite high ( approximately 0.7-0.9), much greater than theta coherence between homotypic sites 3-5 mm distant ( approximately 0.4-0.6) along the long axis. These findings define anatomic variation in both rhythms along the longitudinal axis of the hippocampus, indicate the bilateral CA3/mossy cell projections are the major determinant of theta coherence during REM, and demonstrate that theta coherence varies as a function of anatomical connectivity rather than physical distance. We suggest CA3 and entorhinal inputs interact dynamically to generate theta field potentials and advance the utility of theta and gamma coherence as indicators of hippocampal dynamics.

Revealing past memories: proactive interference and ketamine-induced memory deficits.

Memories of events that occur often are sensitive to interference from memories of similar events. Proactive interference plays an important and often unexamined role in memory testing for spatially and temporally unique events ("episodes"). Ketamine (NMDA receptor antagonist) treatment in humans and other mammals induces a constellation of cognitive deficits, including impairments in working and episodic memory. We examined the effects of the ketamine (2.5-100 mg/kg) on the acquisition, retrieval, and retention of memory in a delayed-match-to-place radial water maze task that can be used to assess proactive interference. Ketamine (2.5-25 mg/kg, i.p.) given 20 min before the sample trial, impaired encoding. The first errors made during the test trial were predominantly to arms located spatially adjacent to the goal arm, suggesting an established albeit weakened representation. Ketamine (25-100 mg/kg) given immediately after the sample trial had no effect on retention. Ketamine given before the test trial impaired retrieval. First errors under the influence of ketamine were predominantly to the goal location of the previous session. Thus, ketamine treatment promoted proactive interference. These memory deficits were not state dependent, because ketamine treatment at both encoding and retrieval only increased the number of errors during the test session. These data demonstrate the competing influence of distinct memory representations during the performance of a memory task in the rat. Furthermore, they demonstrate the subtle disruptive effects of the NMDA antagonist ketamine on both encoding and retrieval. Specifically, ketamine treatment disrupted retrieval by promoting proactive interference from previous episodic representations.