A candidate mechanism underlying the variance of interictal spike propagation.

Synchronous activation of neural networks is an important physiological mechanism, and dysregulation of synchrony forms the basis of epilepsy. We analyzed the propagation of synchronous activity through chronically epileptic neural networks. Electrocorticographic recordings from epileptic patients demonstrate remarkable variance in the pathways of propagation between sequential interictal spikes (IISs). Calcium imaging in chronically epileptic slice cultures demonstrates that pathway variance depends on the presence of GABAergic inhibition and that spike propagation becomes stereotyped following GABA receptor blockade. Computer modeling suggests that GABAergic quenching of local network activations leaves behind regions of refractory neurons, whose late recruitment forms the anatomical basis of variability during subsequent network activation. Targeted path scanning of slice cultures confirmed local activations, while ex vivo recordings of human epileptic tissue confirmed the dependence of interspike variance on GABA-mediated inhibition. These data support the hypothesis that the paths by which synchronous activity spreads through an epileptic network change with each activation, based on the recent history of localized activity that has been successfully inhibited.

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.

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.

Intraseptal tacrine-induced disruptions of spatial memory performance.

The medial septal nucleus regulates the physiology and emergent functions (e.g., memory formation) of the hippocampal formation. This nucleus is particularly rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive enhancing drugs. Several studies have examined the direct effects of intraseptal cholinomimetic treatments and the results have been somewhat conflicting with both promnestic and amnestic effects. Several variables (e.g., age, task difficulty, timing of drug administration) may influence treatment outcome. The present study examined the effects of intraseptal infusion of the acetylcholinesterase inhibitor tacrine (0-25 microg/0.5 microl) on spatial memory performance. Tacrine was infused into the medial septum just prior to testing. Tacrine infusions did not significantly affect the number of correct choices in the first eight entries, or the number of correct choices until an error. This treatment did not alter the angle of arm entries, or impair the animals' ability to complete the task (enter all baited arms). However, tacrine produced a linear dose-dependent increase in errors, doubling (12.5 microg) and tripling (25.0 microg) the number of errors made before rats completed the task. The deficit demonstrates that activation of intraseptal cholinergic receptors can disrupt spatial memory performance. These findings are discussed with regards to septohippocampal-dependent memory processes and the development of therapeutic strategies in the treatment of age-related memory disorders.

Within-subject memory decline in middle-aged rats: effects of intraseptal tacrine.

A longitudinal design was used to examine spatial working memory performance in aging Long-Evans rats on a 12-arm, delayed-non-match-to-sample radial maze task. Compared to performance at 12-13 months of age, the same rats exhibited a significant performance deficit at 15-16 months of age across all retention intervals (1.5-10h). All rats exhibited some degree of decline, and no rat performed as well as they had 3 months earlier. This early onset deficit may relate to the degree of difficulty required to perform accurately in a task that maximizes both spatial information processing and flexible working memory representations. Following our observation, rats were implanted with a chronic cannula aimed at the medial septal nucleus. Acute intraseptal tacrine treatments (0.0-25 micrograms/0.5 microl) did not significantly affect any index of performance. Rats exhibited further memory decline over the course of testing (up to 20 months of age). Detection of early onset dysfunction could allow for experimental analysis of underlying mechanisms and therapeutic strategies early in the course of age-related changes.

Intraseptal tacrine can enhance memory in cognitively impaired young rats.

The medial septum is rich in cholinergic receptors and is a target for the development of cognitive enhancers. Intraseptal cholinomimetics have produced both promnesic and amnesic effects. Several variables (e.g. age, task difficulty) may influence treatment outcome. The present study examined the effects of intraseptal tacrine in a group of young cognitively impaired rats. These rats had been culled from a difficult radial maze task because they could not achieve criterion performance. Tacrine (0-12.5 microg/0.5 microl) enhanced radial maze performance in these animals. This effect contrasts with findings that intraseptal choliomimetics often have no effect or disrupt performance in young rats. Understanding the conditions in which cholinomimetics are promnesic is important for the further development of cognitive enhancers.

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.

Intraseptal infusion of the cholinergic agonist carbachol impairs delayed-non-match-to-sample radial arm maze performance in the rat.

The medial septal nucleus regulates the physiology and emergent functions (e.g., memory formation) of the hippocampal formation. This nucleus is particularly rich in cholinergic receptors and is a putative target for the development of cholinomimetic cognitive enhancing drugs. A large number of studies have demonstrated that direct intraseptal drug infusions can produce amnestic or promnestic effects. While a few studies have examined the effects of direct intraseptal infusion of cholinomimetics on spatial memory performance (with drug "on-board" at the time of testing), the effects of post-acquisition infusions have not been assessed. We hypothesized that post-acquisition intraseptal infusion of cholinomimetics, by promoting hippocampal theta and suppressing the occurrence of hippocampal sharp waves, may disrupt the long-term retention and consolidation of memory. The present study examined the effects of intraseptal infusion of the cholinergic agonist carbachol in a delayed-non-match-to-sample radial maze task. Treatments were administered immediately following (within 1 min) the sample session with a retention session 2 h later. Carbachol infusions (12.5-125 ng in 0.5 microl) produced a linear dose-dependent decrease in correct entries and increase in retroactive errors, without any change in proactive errors or latency-per-choice. These findings suggest that post-acquisition intraseptal cholinergic treatments can produce amnesia. These findings are discussed with regard to multi-stage models of hippocampal-dependent memory formation and the further development of therapeutic strategies in the treatment of mild cognitive impairment as well as age-related cognitive decline and Alzheimer's dementia.