L. Stan Leung

Generation of Theta and Gamma Rhythms in the Hippocampus

In the behaving rat, theta rhythm was dominant during walking and rapid-eye-movement sleep, while irregular slow activity predominated during immobility and slow-wave sleep. Oscillatory evoked potentials of 20-50 Hz and spontaneous fast (gamma) waves were more prominent during theta compared with non-theta behaviors. The oscillations were simulated by a systems model with recurrent inhibition. The model also predicts a behaviorally dependent inhibition, which was confirmed experimentally using paired-pulse responses. Paired-pulse facilitation (PPF) of the population spikes in CA1 was larger during walking than immobility, mostly mediated by a cholinergic input. Spike responses in vitro were characterized by a relative lack of inhibition or disinhibition compared with the behaving rat. The two-input, two-dipole model of the theta rhythm in CA1 is reviewed. Afferents to the CA1 pyramidal cells are assumed to be rhythmic and consist of atropine-sensitive and atropine-resistant inputs driving the somata and distal dendrites, respectively. The atropine-sensitive theta rhythm was mainly caused by a series of Cl- mediated inhibitory postsynaptic potentials (IPSPs) on pyramidal cells. It is suggested that previous claims of the participation of excitatory postsynaptic potentials (EPSPs) and not IPSPs in the intracellular recordings in vivo were flawed. Single cell recordings in vitro suggested that intrinsic voltage-dependent membrane potential oscillations modulate the response to a theta-frequency driving. Membrane potentials of pyramidal cells in vitro showed resonance in the theta frequency range.

Behavior-dependent evoked potentials in the hippocampal CA1 region of the rat. I. Correlation with behavior and egg

As an alternative approach to the study of hippocampal function in relation to behavior, the averaged evoked potentials (AEPs) evoked by electrical stimulation of the Schaffer collaterals (SCH), the alveus and the contralateral hippocampus were recorded at various depths in the hippocampal CA1 region of freely moving rats with chronically implanted electrodes. Significant correlations between AEPs, behavior and EEG were found. At one end of the continuum of AEPs were those recorded during large irregular activity (LIA), an EEG pattern associated with slow-wave sleep or awake-immobility. These AEPs had large early peak and low-amplitude late peaks. At the order end of the continuum, during high frequency theta EEG associated with behaviors such as walking, postural change or phasic paradoxical sleep. AEPs had a smaller early peak, increased later peak(s) and appeared oscillatory. The evoked population spike, a synchronous postsynaptic firing of CA1 neurons, was smaller during behaviors associated with theta than during those associated with LIA. It is postulated that a recurrent inhibitory circuit within the hippocampus can account for the change of the AEPs with EEG and behavior and with stimulus intensity. During theta EEG, the negative feedback may increase such that the evoked population excitatory postsynaptic potential and the evoked population spike decrease and ascillatory response is more readily elecited. The excitability state of hippocampal CA1 may be described by the negative feedback gain in this model.

Functional Networks in the Anesthetized Rat Brain Revealed by Independent Component Analysis of Resting-State fMRI

The rodent brain is organized into functional networks that can be studied through examination of synchronized low-frequency spontaneous fluctuations (LFFs) of the functional magnetic resonance imaging -blood-oxygen-level-dependent (BOLD) signal. In this study, resting networks of LFFs were estimated from the whole-brain BOLD signals using independent component analysis (ICA). ICA provides a hypothesis-free technique for determining the functional connectivity map that does not require a priori selection of a seed region. Twenty Long-Evans rats were anesthetized with isoflurane (1%, n = 10) or ketamine/xylazine (50/6 mg . kg(-1) . h(-1) ip, n = 10) and imaged for 5-10 min in a 9.4 T MR scanner without experimental stimulation or task requirement. Independent, synchronous LFFs of BOLD signals were found to exist in clustered, bilaterally symmetric regions of both cortical and subcortical structures, including primary and secondary somatosensory cortices, motor cortices, visual cortices, posterior and anterior cingulate cortices, hippocampi, caudate-putamen, and thalamic and hypothalamic nuclei. The somatosensory and motor cortices typically demonstrated both symmetric and asymmetric components with unique frequency profiles. Similar independent network components were found under isoflurane and ketamine/xylazine anesthesia. The report demonstrates, for the first time, 12 independent resting networks that are bilaterally synchronous in different cortical and subcortical areas of the rat brain.

Behavior-dependent evoked potentials in the hippocampal CA1 region of the rat. II. Effect of eserine, atropine, ether and pentobarbital

The correlations of the rats behaviors and the hippocampal EEG with the averaged evoked potentials (AEPs) evoked by the Schaffer collaterals in the hippocampal CA1 region of the rat were studied after intraperitoneal injections of several drugs known to affect hippocampal EEG. Ether and eserine induced continuous train of rhythmical slow activity (RSA) of 5-6/sec in the hippocampal EEG, during which the AEPs showed waveforms intermediate between those elicited during large irregular activity (LIA) in the awake, immobile control and those elicited during walking in the control. Low dose nembutal and atropine induced high amplitude LIA during immobility, resembling EEG during slow-wave sleep (SWS). The AEPs during these LIA states, and that during LIA of wake-immobility were of similar waveforms. The AEP waveforms are proposed to form a continuum which corresponds to the continuum of EEG from high amplitude LIA to RSA of increasing frequency. AEP waveforms do not depend only on walking or similar movements which correlate with high frequency RSA. Atropine sulfate (25-50 mg/kg i.p.) severely dampened the oscillations in the AEPs of rats during walking or similar movements, even though the high frequency RSA was essentially unaffected. The difference between AEPs during immobility and those during walking was markedly reduced after atropine, even though the EEG-behavior relationship persisted. The effect of atropine on AEPs may be interpreted as a direct effect on the hippocampus which is apparently inconsistent with present knowledge. If the effect was on inputs from the brain stem or the septum to the hippocampus, the hypothesis that there are two pharmacological types of RSA (atropine-sensitive and -resistant) requires re-definition and re-examination.

Selective theta-synchronization of choice-relevant information subserves goal-directed behavior.

Theta activity reflects a state of rhythmic modulation of excitability at the level of single neuron membranes, within local neuronal groups and between distant nodes of a neuronal network. A wealth of evidence has shown that during theta states distant neuronal groups synchronize, forming networks of spatially confined neuronal clusters at specific time periods during task performance. Here, we show that a functional commonality of networks engaging in theta rhythmic states is that they emerge around decision points, reflecting rhythmic synchronization of choice-relevant information. Decision points characterize a point in time shortly before a subject chooses to select one action over another, i.e., when automatic behavior is terminated and the organism reactivates multiple sources of information to evaluate the evidence for available choices. As such, decision processes require the coordinated retrieval of choice-relevant information including (i) the retrieval of stimulus evaluations (stimulus–reward associations) and reward expectancies about future outcomes, (ii) the retrieval of past and prospective memories (e.g., stimulus–stimulus associations), (iii) the reactivation of contextual task rule representations (e.g., stimulus–response mappings), along with (iv) an ongoing assessment of sensory evidence. An increasing number of studies reveal that retrieval of these multiple types of information proceeds within few theta cycles through synchronized spiking activity across limbic, striatal, and cortical processing nodes. The outlined evidence suggests that evolving spatially and temporally specific theta synchronization could serve as the critical correlate underlying the selection of a choice during goal-directed behavior.

Resting-state networks in the macaque at 7 T ☆

Assessment of brain connectivity has revealed that the structure and dynamics of large-scale network organization are altered in multiple disease states suggesting their use as diagnostic or prognostic indicators. Further investigation into the underlying mechanisms, organization, and alteration of large-scale brain networks requires a homologous animal model that would allow neurophysiological recordings and experimental manipulations. The current study presents a comprehensive assessment of macaque resting-state networks based on evaluation of intrinsic low-frequency fluctuations of the blood oxygen-level-dependent signal using group independent component analysis. Networks were found underlying multiple levels of sensory, motor, and cognitive processing. The results demonstrate that macaques share remarkable homologous network organization with humans, thereby providing strong support for their use as an animal model in the study of normal and abnormal brain connectivity as well as aiding the interpretation of electrophysiological recordings within the context of large-scale brain networks.

Radial maze performance following hippocampal kindling

The relation between hippocampal epileptiform activity and 8-arm radial maze performance was assessed following repetitive afterdischarges (ADs) evoked by stimulation of the hippocampal CA1 region (kindling). Hippocampal kindling, whether to stage V (generalized) convulsions or to a preconvulsive stage, induced deficits in radial maze performance, evaluated by correct arm entries in 8 choices or total maze run (trial) time. The deficits persisted at least until 21 days after the last AD. Hippocampal interictal spikes (ISs) were induced by kindling, but the rate of ISs declined to near zero in a few days. The rate or presence of ISs was not related to maze performance.

Effects of hippocampal kindling on paired-pulse response in CA1 in vitro.

Kindled rats were given high-frequency stimulations delivered to hippocampal CA1 on one side to induce afterdischarges (ADs). Control rats received the same number of pulses of a similar intensity at 0.17 Hz (low-frequency stimulations (LFSs)). On 1-2 days or on 21-23 days after fifteen ADs/LFSs (delivered hourly, 5 times a day over 3 days), hippocampal slices were prepared and incubated in vitro, with the experimenter blind to the previous history of stimulation of the rat. Extracellular responses following single or paired-pulse stimulation of the Schaffer collaterals (stratum radiatum) were recorded at the CA1 cell layer in vitro, and analyzed as population excitatory postsynaptic potentials (EPSPs) and population spikes. At 1.5, 2 or 4 times the response threshold, and on either day 1 or day 23 after the last AD/LFS, the paired-pulse response at interpulse intervals of 30-200 ms was significantly larger for the kindled group of slices than for the control group (ANOVA, typically P less than 0.0001), for either the population spike or the population EPSP. Stimulus thresholds for the evoked response did not differ between kindled and control group of slices. The population EPSP and spike in response to a single pulse were enhanced (as compared to the control group) on day 1 but not on day 23 after kindling. The facilitation of paired-pulse response may be interpreted as caused by a decrease in postsynaptic (and possibly presynaptic) inhibition in the hippocampal CA1 region, which persisted to at least 3 weeks after hippocampal kindling.

Hippocampal Melatonin Receptors Modulate Seizure Threshold

Summary:  Purpose: The pineal hormone melatonin has been shown to enhance hippocampal excitability. We therefore investigated whether inactivation of hippocampal melatonin receptors affects behavioral seizures.

Lateral entorhinal, perirhinal, and amygdala‐entorhinal transition projections to hippocampal CA1 and dentate gyrus in the rat: A current source density study

In urethane‐anesthetized rats, cortical regions which provide distal dendritic excitation of the dentate gyrus and CA1 of the dorsal hippocampus were studied using current source density analysis. Electrical stimulation of the lateral perforant path (LPP) in the lateral angular bundle, lateral entorhinal cortex (LEC), and amygdala‐entorhinal transition (TR) resulted in a current sink in the outer molecular layer of the dentate gyrus accompanied by proximal sources; this sink‐source pattern is distinctly different from the source‐sink‐source pattern evoked by medial perforant path stimulation. The progressive decrease of the sink latency following stimulation of the TR, LEC, and LPP (11.6, 7.8, and 3.6 ms, respectively, at the dorsal blade of the dentate gyrus) suggests a possible sequence of orthodromic activation of these structures. Stimulation of the LEC or TR (collectively termed cortical stimulation) differed from LPP (fiber) stimulation. A low threshold and small chronaxie were characteristic of fiber rather than cortical stimulation. In addition, cortical stimulation, possibly through excitation of intracortical circuits, evoked larger paired‐pulse facilitation of the excitatory postsynaptic currents in dentate gyrus and more symmetric excitation of the dorsal and ventral blades of the dentate gyrus as compared to fiber stimulation. Stimulation of the perirhinal cortex (PRh) evoked a short‐latency sink in the outer molecular layer of the dentate gyrus with no paired‐pulse facilitation, similar to fiber stimulation. A distal dendritic CA1 sink was observed after LPP but not after PRh stimulation. An ibotenic acid injection that lesioned almost all the cells in the perirhinal cortex confirmed the hypothesis that PRh stimulation activated fibers of passage, perhaps in the rostral ventrolateral angular bundle. We conclude that the PRh does not provide a significant excitatory input to the DG or CA1. We have found distinct dendritic excitation of the dentate gyrus by the lateral versus medial perforant paths, and by fiber (LPP and MPP) versus cortical (LEC and TR) stimulation. We also emphasize that processing in the entorhinal cortex is important in the temporal shaping of the signals afferent to the hippocampus. Hippocampus 1997;7:643–655. © 1997 Wiley‐Liss, Inc.