Caffeine consumption disrupts hippocampal long-term potentiation in freely behaving rats.

Caffeine, one of the most commonly consumed psychoactive substances in the world, has long been known to alter neurological functions, such as alertness, attention, and memory. Despite caffeine's popularity, systematic investigations of its effects on synaptic plasticity in the brain are still lacking. Here we used a freely behaving rodent model of long-term potentiation (LTP), a frequently studied form of synaptic plasticity, to assess the effects of caffeine consumption on hippocampal plasticity. LTP, which is a persistent increase in the strength of synaptic connections between neurons, is a cellular mechanism widely considered to underlie the processes of learning and memory. A group of 10-week-old Sprague-Dawley rats were administered caffeine (1 g/L) in their drinking water 3 weeks prior to collection of electrophysiological data. Another group of age-matched animals received tap water and served as controls. Stimulating and recording electrodes were chronically implanted in the perforant pathway (PP) and dentate gyrus (DG) region of the hippocampus, respectively, to permit stable electrophysiological recordings of synaptic transmission at this synapse. Population spike amplitude (PSA) measures of LTP induction and duration were acquired in vivo while animals were freely behaving using a well-established electrophysiological recording protocol. Results indicate caffeine-treated rats (n = 9) had a significantly (P < 0.05) reduced level of LTP induction compared with controls (n = 10). More studies are needed to identify the exact mechanism through which caffeine alters LTP induction in this freely behaving model of synaptic plasticity.

Developmental differences of dimension complexity of hippocampal EEG during REM sleep.

This paper uses spectral analysis and correlation dimension index to examine the developmental differences between the EEG measured from two hippocampal subfields, CA1 and the dentate gyrus. The study was focused on the hippocampal EEG during the vigilance state of REM sleep in freely moving rats of 15 and 90 days of age. Power spectra, magnitude-squared coherence, and correlation dimension were estimated. The correlation dimension adds a new interpretation from the nonlinear dynamics perspective, and we found that there are no significant developmental differences between the granule cells of the dentate gyrus and the pyramidal cells of area CA1 when the theta activity was present during REM sleep.

Application of independent component analysis to remove linear dependencies in EEG recorded in hippocampus.

Linear cross-spectral and nonlinear cross-bispectral analysis techniques were applied to EEG data recorded simultaneously in two subfields (CA1 and dentate gyrus) of the hippocampus in freely behaving neonatal rats during REM sleep. Linear dependencies between the two sites were specifically removed using independent component analysis (ICA). The cross-spectrum and the cross-bispectrum computed prior to ICA processing were compared with those after ICA processing to determine its effects. Our results indicate that ICA almost completely extracts the linear relationship in the theta frequency band between CA1 and the dentate gyrus. It is noted also that ICA processing significantly decreases the quadratic phase coupling (QPC) between the two hippocampal subfields.

Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats.

Ketogenic diets are low-carbohydrate, sufficient protein, high-fat diets with anticonvulsant activity used primarily as a treatment for pediatric epilepsy. The anticonvulsant mechanism is thought to involve elevating inhibition and/or otherwise limiting excitability in the brain. Such a mechanism, however, might also significantly affect normal brain activity and limit synaptic plasticity, effects that would be important to consider in the developing brain. To assess ketogenic diet effects on synaptic transmission and plasticity, electrophysiological recordings were performed at the perforant path/dentate gyrus synapse in awake, freely-behaving juvenile male rats. Electrodes were implanted 1 week prior to recording. Animals were fed regular chow or a ketogenic diet ad libitum for 3 weeks before recording. Although the ketogenic diet did not significantly alter baseline excitability (assessed by input-output curves) or short-term plasticity (using the paired-pulse ratio), it did reduce the magnitude of long-term potentiation at all poststimulation timepoints out to the last time measured (48 h). The results suggest an effect of ketogenic diet-feeding on the induction magnitude but not the maintenance of long-term potentiation. The lack of effect of the diet on baseline transmission and the paired-pulse ratio suggests a mechanism that limits excitation preferentially in conditions of strong stimulation, consonant with clinical reports in which the ketogenic diet alleviates seizures without a major impact on normal brain activity. Limiting plasticity in a seizure-susceptible network may limit seizure-induced epileptogenesis which may subserve the ongoing benefit of the ketogenic diet in epilepsy.

Long-term potentiation of perforant pathway-dentate gyrus synapse in freely behaving mice.

Studies of long-term potentiation of synaptic efficacy, an activity-dependent synaptic phenomenon having properties that make it attractive as a potential cellular mechanism underlying learning and information storage, have long been used to elucidate the physiology of various neuronal circuits in the hippocampus, amygdala, and other limbic and cortical structures. With this in mind, transgenic mouse models of neurological diseases represent useful platforms to conduct long-term potentiation (LTP) studies to develop a greater understanding of the role of genes in normal and abnormal synaptic communication in neuronal networks involved in learning, emotion and information processing. This article describes methodologies for reliably inducing LTP in the freely behaving mouse. These methodologies can be used in studies of transgenic and knockout freely behaving mouse models of neurodegenerative diseases.

Stimulation of perforant path fibers induces LTP concurrently in amygdala and hippocampus in awake freely behaving rats.

Long-term potentiation (LTP) which has long been considered a cellular model for learning and memory is defined as a lasting enhancement in synaptic transmission efficacy. This cellular mechanism has been demonstrated reliably in the hippocampus and the amygdala-two limbic structures implicated in learning and memory. Earlier studies reported on the ability of cortical stimulation of the entorhinal cortex to induce LTP simultaneously in the two sites. However, to retain a stable baseline of comparison with the majority of the LTP literature, it is important to investigate the ability of fiber stimulation such as perforant path activation to induce LTP concurrently in both structures. Therefore, in this paper we report on concurrent LTP in the basolateral amygdala (BLA) and the dentate gyrus (DG) subfield of the hippocampus induced by theta burst stimulation of perforant path fibers in freely behaving Sprague-Dawley rats. Our results indicate that while perforant path-evoked potentials in both sites exhibit similar triphasic waveforms, the latency and amplitude of BLA responses were significantly shorter and smaller than those of DG. In addition, we observed no significant differences in either the peak level or the duration of LTP between DG and BLA.

A ketogenic diet reduces long-term potentiation in the dentate gyrus of freely behaving rats.

Ketogenic diets are very low in carbohydrates and can reduce epileptic seizures significantly. This dietary therapy is particularly effective in pediatric and drug-resistant epilepsy. Hypothesized anticonvulsant mechanisms of ketogenic diets focus on increased inhibition and/or decreased excitability/excitation. Either of these consequences might not only reduce seizures, but also could affect normal brain function and synaptic plasticity. Here, we characterized effects of a ketogenic diet on hippocampal long-term potentiation, a widely studied form of synaptic plasticity. Adult male rats were placed on a control or ketogenic diet for 3 wk before recording. To maintain the most physiological conditions possible, we assessed synaptic transmission and plasticity using chronic in vivo recordings in freely behaving animals. Rats underwent stereotaxic surgery to chronically implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path; they recovered for 1 wk. After habituation and stable baseline recording, 5-Hz theta-burst stimulation was delivered to induce long-term potentiation. All animals showed successful plasticity, demonstrating that potentiation was not blocked by the ketogenic diet. Compared with rats fed a control diet, rats fed a ketogenic diet demonstrated significantly diminished long-term potentiation. This decreased potentiation lasted for at least 48 h. Reduced potentiation in ketogenic diet-fed rats is consistent with a general increase in neuronal inhibition (or decrease in excitability) and decreased seizure susceptibility. A better understanding of the effects of ketogenic diets on synaptic plasticity and learning is important, as diet-based therapy is often prescribed to children with epilepsy.

Neonatal isolation stress alters bidirectional long-term synaptic plasticity in amygdalo-hippocampal synapses in freely behaving adult rats.

The basolateral amygdala (BLA) is known to be involved in emotional and stress responses, while the dentate gyrus (DG), a subfield of the hippocampus, is implicated in learning and memory. Together, the BLA-DG neuronal pathway is thought to link memory with emotional and physiological stress responses. To assess whether neonatal isolation, a known early life stressor, has enduring effects on bidirectional neuroplasticity in adulthood, changes in long-term potentiation (LTP) and long-term depression (LTD) of BLA-DG synapses were recorded in neonatally isolated and non-handled freely behaving adult male rats. Rats isolated (ISO) from their mother and each other for 1 h daily from postnatal days 2-9 were allowed to mature to adulthood at which time they were chronically implanted with stimulating electrodes in the BLA and recording electrodes in the DG via stereotaxic surgery. A second group of rats which received no isolation treatment and which were not handled (NH) during the neonatal period underwent the same surgical procedures and served as the control group. Following a 1-week postsurgical recovery period, either LTP (100-pulse, 5-Hz theta-burst stimulation [TBS]) or LTD (900-pulse, 1-Hz low-frequency stimulation [LFS]) was induced in the DG of both groups. ISO rats showed significantly enhanced levels of both LTP and LTD compared to NH counterparts. These results indicate that neonatal isolation stress alters bidirectional neural plasticity in BLA-DG synapses, which may help to clarify the development of neural mechanisms linking emotional and stress responses in the amygdala with memory consolidation and information processing in the hippocampus.

Bidirectional synaptic plasticity in the dentate gyrus of the awake freely behaving mouse.

There is significant interest in in vivo synaptic plasticity in mice due to the many relevant genetic mutants now available. Nevertheless, use of in vivo models remains limited. To date long-term potentiation (LTP) has been studied infrequently, and long-term depression (LTD) has not been characterized in the mouse in vivo. Herein we describe protocols and improved methodologies we developed to record hippocampal synaptic plasticity reliably from the dentate gyrus of the awake freely behaving mouse. Seven days prior to recording, we implanted microelectrodes encapsulated within a lightweight, low profile head stage assembly. On the day of recording, we induced either LTP or LTD in the awake freely behaving animal, and monitored subsequent changes in population spike amplitude for at least 24h. Using this protocol we attained 80% success in inducing and maintaining either LTP or LTD. Recording from a chronic implant using this improved methodology is best suited to reveal naturally occurring brain activity and avoids both acute effects of local electrode insertion and drifts in neuronal excitability associated with anesthesia. Ultimately a reliable freely behaving mouse model of bi-directional synaptic plasticity is invaluable for full characterization of genetic models of disease states and manipulations of the mechanisms implicated in learning and memory.

Effects of stimulus frequency and age on bidirectional synaptic plasticity in the dentate gyrus of freely moving rats.

We investigated the frequency-dependent transition from homosynaptic long-term depression (LTD) to long-term potentiation (LTP) at the lateral perforant pathway/dentate gyrus synapse in adult (90 days of age) and immature (15 days of age) awake, freely moving rats. Dentate-evoked field potentials were recorded and analyzed using the population spike amplitude and the field EPSP slope measures following sustained stimulation (900 pulses) of the lateral perforant pathway at various frequencies (1, 3, 7, 30, 50, or 200 Hz). Our results indicate that both the strength and the direction (LTP or LTD) of synaptic plasticity vary as a function of activation frequency: sustained low-frequency stimulation ranging from 1 to 7 Hz results in depression of activated synapses, whereas high-frequency stimulation (30-200 Hz) produces potentiation. In addition, a significant (P < 0.01) ontogenetic shift in the frequency of transition from LTD to LTP was observed; the transition frequency in immature animals was significantly lower than that obtained in adult animals. These observations agree strongly with the prediction of the Bienenstock-Cooper-Munro theory of synapse modification, indicating perhaps a neurophysiological basis for this theoretical model of learning in the dentate gyrus of awake behaving rats.