Non-rhythmical hippocampal units, theta rhythm and afferent stimulation

Physostigmine induced theta (θ) rhythm and unit activity were recorded from dorsal hippocampus in immobilized locally anesthetized rats. Two functionally different types of cells were identified, Type 1 which fired in rhythmical bursts phase-locked with γ cycles, and Type 2 which were non-rhythmical. Most of the units (80%) were Type 2 and either had bursting (40%) or non-bursting discharge patterns. Correlations between the θ rhythm and Type 2, Type 1 and Type 2, and between pairs of Type 2 cells were studied. Modifications of correlations by afferent stimulation were also analyzed. The principal findings was that in the presence of θ about half of the Type 2 cells revealed a degree of phase-locking with the rhythm. This finding suggests a caused relationship between both phenomena. Crosscorrelograms between Type 1 and 2 discharges, when positive, showed a symmetrical periodicity suggesting that Type 2 cells might function as an hippocampal output. The activity of Type 2 pairs, positively crossconelated in nearly two thirds of the cases, revealed excitatory interactions. Hippocampal afferent stimulation reset θ activity in phase, modified the temporal relationships between cells and with the θ rhythm, and changed the Type 2 discharge pattern. The above results indicate that θ-related Type 2 cells carry information representing θ rhythmicity. Phase-relationships between Type 2 cells and θ, and their modifications by hippocampal afferent activity may be necessary to establish time-relationships with other brain structures.     

Colchicine-induced deafferentation of the hippocampus selectively disrupts cholinergic rhythmical slow wave activity

It has been proposed that hippocampal rhythmical slow wave activity (RSA or theta-rhythm) induced by sensory stimulation (atropine-sensitive theta) is generated by the cholinergic septo-hippocampal system. Although ablations of the septum or its projections to the hippocampus disrupt hippocampal RSA, such non-selective lesions damage both cholinergic and non-cholinergic septo-hippocampal inputs. The present study assesses the effects of a selective septal neurotoxic lesion on hippocampal electrical activity. Colchicine, which has been reported to be selectively toxic to cholinergic neurons in the medial septum, was injected into the right lateral ventricle, and electrodes were implanted bilaterally into the dorsal hippocampus of female Sprague-Dawley rats. Hippocampal electrical activity was recorded 10-14 days later from the ipsilateral (colchicine-treated) and contralateral (control) hemispheres during locomotor activity or immobility. RSA ranging from 6.3 to 8.7 Hz was evoked in both hippocampi during mobility. Following i.p. administration of an anesthetic dose of urethane, hippocampal RSA at a frequency of 4 Hz could be elicited in the control hemisphere (n = 12) of all animals by pinching the tail. RSA was absent in 6 of 9 animals in the colchicine-treated hemisphere. RSA from control and treated hemispheres persisting after urethane administration was abolished by 5 mg/kg of scopolamine, thus verifying its cholinergic nature. A decrease in the number of choline acetyltransferase (ChAT)-immunoreactive neurons in the medial septum and a depletion of acetylcholinesterase (AChE)-staining in the hippocampus were evident in the hemisphere ipsilateral to colchicine administration. These data support the septal pacemaker hypothesis of hippocampal theta-rhythm and further demonstrate the neurotoxic effect of colchicine on septo-hippocampal cholinergic neurons by the induction of a functional alteration. The selective disruption of cholinergic neurons in the medial septum by colchicine provides a means to dissociate the contribution of septal cholinergic and non-cholinergic components to hippocampal electrical activity.     

Effects of atropine on hippocampal theta cells and complex-spike cells

The medial septal nuclei are essential for the naturally occurring hippocampal theta rhythm. Evidence that the rhythmic activity of the septum is carried via cholinergic afferents to the hippocampus has been: (a) the existence of a cholinergic septo-hippocampal projection, and (b) the sensitivity of one type of theta rhythm to antimuscarinic agents or cholinergic depletion. The muscarinic action of acetylcholine on pyramidal cells, however, is too slow to carry even a 4 Hz signal. Recent in vitro studies have confirmed a fast excitatory response by some hippocampal interneurons to muscarinic agonists. In urethane anesthetized rats, iontophoretic application of atropine to 17 hippocampal theta cells (presumed interneurons) during the theta rhythm, reduced their firing rates to an average of 24% of control rates. The effect of iontophoretic atropine application to 4 CA1 complex-spike cells (presumed pyramidal cells) was a selective elimination of their bursting activity with no significant effect on overall firing rate. The data suggest that: (1) interneuronal firing, during the hippocampal theta rhythm, is dominated by an excitatory cholinergic input and not by excitatory collaterals of pyramidal cells; and (2) somatic burst firing by CA1 pyramidal cells requires the presence of acetylcholine.     

Separation of hippocampal theta dipoles by partial coherence analysis in the rat

In order to separate the effect of different theta generators in the hippocampus and to characterize the pattern of relationships between them, in this study, we calculated the coherence that remains between EEG signals, recorded (1) in the stratum oriens of the CA1 region and (2) close to the hippocampal fissure in the dentate gyrus of the right or left hippocampus, after the variations, common also for a third recording site is eliminated (partialization). We found that in both anesthetized and freely moving rats, there is a selective high correlation (coherence) between theta rhythmic activities of contralateral homonymous sites of the hippocampus. The coherence between field potentials recorded in ipsilateral superficial and deep layers was eliminated when allowance was made for any of the contralateral hippocampal recordings. On the other hand, coherence between contralateral homonymous theta dipoles did not decrease when partialized by a heteronymous hippocampal EEG signal. The present results support earlier findings on multiple hippocampal theta dipoles and indicate that they can be separated using partial coherence analysis. The left and right superficial and deep dipoles oscillate as if they formed two separate systems one extending over the superficial CA1 layers on both sides and the other consisting of the left and right deep hippocampal theta dipoles. The results also suggest an important role of the commissural projections in interhemispheric theta synchronization.     

The effects of serotonergic stimulation on hippocampal and neocortical slow waves and behavior

The effect of central serotonergic stimulation on hippocampal and neocortical electrical activity and behavior was studied in freely moving rats by administering: (a) tranylcypromine followed by tryptophan, (b) fluoxtine followed by 5-hydroxytryptophan, or (c) p-chloroamphetamine alone. In all rats, scopolamine-resistant hippocampal thytmical slow activity (RSA), thought to be dependent on brain serotonin, maintained its normal relation to behavior, occuring in close correlation with Type 1 behaviors (postular changes, turning of the head, walking). This RSA was generally absent during stereotyped behavior (head weaving, forepaw treading, hindlimb splaying and tremor). Scopolamine-resistant neocortical low-voltage fast activity (LVFA), also thought to be dependent on brain serotonin, was present during Type 1 behaviors and also during stereotyped behavior.Most rats developed a full stereotyped behavior syndrome had behavioral and electrocortical seizures which were associated with a reduction in the amplitude of hippocampal activity. These seizures were suppressed by methylsergide or benserazide. Metergoline (and methylsergide to a lesser extent) suppressed the stereotypic behaviors of the serotonin syndrome, resulting in a striking increase in the locomotion caused by central serotonergic stimulation. Such locomotion was accompanied by RSA and LVFA. It was concluded that increased serotonergic activity in the CNS causes an increase in motor activity and a correlated increase in scopolamine-resistant hippocampal RSA and scopolamine-resistant neocortical LVFA and suggested that metergoline blocks serotonin receptors mediating stereotyped behaviors, thereby permitting the expression of serotonin-mediated locomotion.     

The effect of diazepam on hippocampal EEG in relation to behavior

Male mice of the BALB/cByJ and C57BL/6 strains were implanted with electrodes in the CA1 area of the hippocampus to record rhythmic slow-wave activity (RSA) or 'theta' EEG activity. The EEG spectral characteristics and the animal's motor behavior were studied while the animals walked on a moving belt (2.2 cm/s) both before and after i.p. injections of diazepam (Valium, 2 mg/kg) or vehicle. EEG spectral analyses were carried out on-line by computer. Diazepam produced a dissociation of locomotion and RSA. (1) Uninjected and vehicle-injected mice showed typical RSA (7-8 Hz) while walking. (2) Under diazepam, 7-8 Hz RSA virtually disappeared and was replaced in the temporally averaged records by RSA with a sharp, narrow-band peak at 4-5 Hz. (3) This lower-frequency RSA was associated with immobility if, and only if, the immobility immediately followed walking. This was true whether the animal itself stopped walking or the experimenter stopped the moving belt. This theta activity predominated for about 30 s and had disappeared after 2 min. Locomotion, on the other hand, was accompanied by irregular EEG activity. (4) Scopolamine (i.p. 1 mg/kg), a cholinergic blocker, greatly reduced the diazepam-induced 4-5 Hz RSA, but also partially restored 7-8 Hz RSA. The possibility that the effects of diazepam on hippocampal EEG involve changes in septohippocampal cholinergic activity is discussed.     

Task-dependent effects of intracranial hippocampal stimulation on human memory and hippocampal theta power

BackgroundDespite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance.ObjectiveWe hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity.MethodsTo investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks – a word pair associative memory task and a single item memory task.ResultsHippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance.ConclusionsWe show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.     

Neonatal vs. adult unilateral hippocampal lesions: differential alterations in contralateral hippocampal theta rhythm

Subcortical damage often has more severe consequences in neonates than in adults. For example, unilateral hippocampal lesions in adult rats typically lead to transient memory deficits, whereas neonatal lesions cause lasting learning impairment. We hypothesized that the defects triggered by unilateral damage may include synaptic dysfunction in the contralateral hippocampus. Consequently, we examined the hippocampal theta rhythm, an EEG pattern thought to be associated with learning. Initial comparisons between intact and lesioned rats revealed no obvious differences in basal theta rhythm properties. However, manipulations of ascending brainstem projections to hippocampus with drugs specific for serotonergic, noradrenergic and cholinergic receptors uncovered differences. Antagonism of 5-HT₃ receptors known to promote learning significantly increased theta frequency in controls and adult lesioned rats, but not after neonatal damage. In contrast, blockade of noradrenergic-α₂ receptors had no effect. Antagonism of cholinergic receptors which typically impairs learning disrupted theta and caused irregular, high-amplitude activity that was significantly more pronounced in the lesioned groups. A final approach involved pharmacological facilitation of AMPA receptor-mediated currents, using a drug which enhances memory. This treatment significantly enhanced theta frequency in controls and animals lesioned as adults. In contrast, it failed to do so in rats lesioned at birth. These observations suggest that latent dysfunction in contralateral hippocampal physiology may contribute to the lasting memory deficits seen after unilateral hippocampal lesion in neonates.     

Modulation of cortically induced rhythmical jaw movements by stimulation of the red nucleus in the rat

We study whether stimulation of the red nucleus (RN) can modulate rhythmical jaw movements in rats anesthetized by urethane. Rhythmical jaw movements were induced by repetitive electrical stimulation of the two cortical masticatory areas (area A: the orofacial motor cortex; area P: the insular cortex). Stimuli applied to the RN did influence rhythmical jaw movements induced by stimulation of the A-area. Stimuli applied in the jaw-closing phase increased the amplitude of the jaw-closing movement. Stimuli applied in the jaw-opening phase disturbed the rhythm of jaw movements and induced a small jaw-closing movement. Stimuli applied to the RN did not influence rhythmical jaw movements induced by stimulation of the P-area. These results indicate that the RN is involved in the modulation of rhythmical jaw movements induced by stimulation of the A-area.     

Involvement of GABAergic transmission in the midbrain ventral tegmental area in the regulation of hippocampal theta rhythm

Previously we indicated that the ventral tegmental area (VTA) may belong to the system regulating hippocampal theta rhythm. In the present study, we aimed at assessing the role of the GABAergic system of the VTA in regulation of hippocampal electric activity. Male Wistar rats received unilateral intra-VTA microinjection of either bicuculline (50 ng/0.5 μl, n = 9), muscimol (100 ng/0.5 μl, n = 10) or phaclofen (500 ng/0.5 μl, n = 9). 1-min tail pinch stimulations were applied at 10-min intervals to evoke theta rhythm episodes in hippocampus. We analysed peak power (P_max) and corresponding frequency (F_max) of EEG signal at delta and theta bands. Bicuculline induced theta rhythm in both hippocampi with 0 latency, continuous for ca. 33 min. Phaclofen also induced theta but in this group it appeared with latency (17.45 ± 3.16 min on average), lasted for ca. 33.6 min and during this time was interrupted by periods of irregular activity of variable length. Tail pinch was not applied in these groups. Muscimol induced an opposite effect: depression of theta P_max with simultaneous increase in delta P_max and a decrease in F_max delta during episodes of tail pinch-evoked theta. This effect had variable latency and no return to the control EEG could be observed. We propose that GABA activity in the VTA is of tonic character, so that abolition of this mechanism produces immediate effect, i.e. theta induction (strong by GABA_A and weak by GABA_B receptors blockade), whereas enhancing the already present GABAergic inhibition causes delayed, prolonged changes expressed as gradual loss of theta synchronisation.     

Presynaptic inhibition of Schaffer collateral synapses by stimulation of hippocampal cholinergic afferent fibres

It has been known for decades that muscarinic agonists presynaptically inhibit Schaffer collateral synapses contacting hippocampal CA1 pyramidal neurons. However, a demonstration of the inhibition of Schaffer collateral synapses induced by acetylcholine released by cholinergic hippocampal afferents is lacking. We present original results showing that electrical stimulation at the stratum oriens/alveus with brief stimulus trains inhibited excitatory postsynaptic currents evoked by stimulation of Schaffer collaterals in CA1 pyramidal neurons of rat hippocampal slices. The increased paired-pulse facilitation and the changes in the variance of excitatory postsynaptic current amplitude that paralleled the inhibition suggest that it was mediated presynaptically. The effects of oriens/alveus stimulation were inhibited by atropine, and blocking nicotinic receptors with methyllycaconitine was ineffective, suggesting that the inhibition was mediated via the activation of presynaptic muscarinic receptors. The results provide a novel demonstration of the presynaptic inhibition of glutamatergic neurotransmission by cholinergic fibres in the hippocampus, implying that afferent cholinergic fibres regulate the strength of excitatory synaptic transmission.     

Hippocampal rhythmical slow activity following ibotenic acid lesions of the septal region. I. Relations to behavior and effects of atropine and urethane

The effects of intraseptal injections of various concentrations of ibotenic acid on hippocampal electrical activity were studied in freely moving and urethane-anesthetized rats. Ibotenic acid selectively abolished the atropine-sensitive form of hippocampal rhythmical slow activity (RSA) normally seen during urethane anesthesia. Large amplitude irregular activity (LIA) and RSA in the waking state were somewhat depressed as well. Despite this, clear RSA persisted in the waking state in association with locomotion or struggling (Type 1 behavior). As in normal rats, such RSA was resistant to systemic administration of atropine. Analysis of brain sections stained with gallocyanin or for acetylcholinesterase showed that ibotenic acid produced cell loss in the dorsal lateral septal nucleus and the septohippocampal nucleus. Cells in the medial septal and diagonal band nuclei were resistant to ibotenic acid. The results suggest that intrinsic septal circuitry is critically involved in the generation of the atropine-sensitive (presumably cholinergic) form of RSA. The mechanisms by which LIA and the two forms of RSA are generated in the hippocampus is discussed.     

Mapping the differential effects of procaine on frequency and amplitude of reticularly elicited hippocampal rhythmical slow activity

Hippocampal rhythmical slow activity (RSA, theta) was elicited in urethanized rats by high-frequency stimulation in the reticular formtion. The effects of procaine infusion (0.5 μL, 20% wt/vol) at various loci in the ascending system from pontine reticular formation to the medial septum/diagonal band area were investigated. It was found that procaine injected at points in the ascending system anterior to the supramamillary nucleus, in the region of the medial forebrain bundle or in the medial septum, reduced the amplitude of reticularly elicited RSA but had no effect on its frequency. Procaine injected at points in the ascending system from just anterior to the reticular formation stimulation site, up to, and including the supramamillary nucleus, reduced both the frequency and amplitude of reticularly elicited RSA. These results indicate that the frequency of reticularly elicited RSA is encoded in the supramamillary area, rather than in the medial septum/diagonal band as have previously been suggested.     

Reversed and forward buffering of behavioral spike sequences enables retrospective and prospective retrieval in hippocampal regions CA3 and CA1

We propose a mechanism to explain both retrospective and prospective recall activity found in experimental data from hippocampal regions CA3 and CA1. Our model of temporal context dependent episodic memory replicates reverse recall in CA1, as recently recorded and published [Foster, D., & Wilson, M. (2006). Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature, 440, 680–683], as well as the prospective and retrospective activity recorded in region CA3 during spatial tasks [Johnson, A., & Redish, A. (2006). Neural ensembles in ca3 transiently encode paths forward of the animal at a decision point: a possible mechanism for the consideration of alternatives. In 2006 neuroscience meeting planner. Atlanta, GA: Society for Neuroscience. (Program no. 574.2)]. We suppose that CA3 encodes episodic memory of both forward and reversed sequences of perforant path spikes representing place input. Using a persistent firing buffer mechanism in layer II of entorhinal cortex, simulated episodic learning involves dentate gyrus, layer III of entorhinal cortex, and hippocampal regions CA3 and CA1. Associations are formed between buffered episodic cues, unique temporal context specific representations in dentate gyrus, and episodic memory in the CA3 recurrent network.     

Oscillatory electrographic activity in the hippocampus: A mathematical model

This model of hippocampal function describes the bilaterally symmetrical interactions of the various intrahippocampal populations of neurons that are functionally homogeneous (septal and entorhinal sources of input, granule cells, CA field pyramidal cells, and basket cells). Activity of each homogeneous population is described as a first order nonlinear differential equation. Parameters are simulated, with activity defined in relative units ranging from 0 to 1.0. The 26 equations (13 identified pools in each hemisphere) were solved simultaneously by computer to produce plots of the time course of activity changes in each of the populations. The simulations performed thus far show that the model parallels certain known properties of the system: (1) there is the expected reciprocal relationship between pyramidal cells and basket cells; (2) activity can be made to oscillate or achieve steady-state, simulating EEG “theta” rhythm or low voltage, fast activity; (3) oscillation occurs where it is known to occur (CA₁ pyramidal cells and the dentate region), where it is presumed to occur (in basket cells), and does not occur where it is known not to occur (CA₂ pyramidal cells); (4) there is a narrow range of frequency, and attempts to increase frequency readily terminate oscillation to cause steady-state activity: (5) oscillation requires excitatory drive from the medial septum, whereas entorhinal input is relatively less important: and (6) increases in medial septal activity can increase oscillation frequency. The results also predict certain undiscovered phenomena: (1) there is a major influence of variations in decay rate of activity in various neuronal pools; (2) there is probably an ultra-slow oscillation in the CA₂ area; and (3) the CA₁ projection to the entorhinal cortex seems to be important in modulating frequency and amplitude of theta rhythm.     

Oscillatory electrographic activity in the hippocampus: A mathematical model

This model of hippocampal function describes the bilaterally symmetrical interactions of the various intrahippocampal populations of neurons that are functionally homogeneous (septal and entorhinal sources of input, granule cells, CA field pyramidal cells, and basket cells). Activity of each homogeneous population is described as a first order nonlinear differential equation. Parameters are simulated, with activity defined in relative units ranging from 0 to 1.0. The 26 equations (13 identified pools in each hemisphere) were solved simultaneously by computer to produce plots of the time course of activity changes in each of the populations. The simulations performed thus far show that the model parallels certain known properties of the system: (1) there is the expected reciprocal relationship between pyramidal cells and basket cells; (2) activity can be made to oscillate or achieve steady-state, simulating EEG “theta” rhythm or low voltage, fast activity; (3) oscillation occurs where it is known to occur (CA₁ pyramidal cells and the dentate region), where it is presumed to occur (in basket cells), and does not occur where it is known not to occur (CA₂ pyramidal cells); (4) there is a narrow range of frequency, and attempts to increase frequency readily terminate oscillation to cause steady-state activity: (5) oscillation requires excitatory drive from the medial septum, whereas entorhinal input is relatively less important: and (6) increases in medial septal activity can increase oscillation frequency. The results also predict certain undiscovered phenomena: (1) there is a major influence of variations in decay rate of activity in various neuronal pools; (2) there is probably an ultra-slow oscillation in the CA₂ area; and (3) the CA₁ projection to the entorhinal cortex seems to be important in modulating frequency and amplitude of theta rhythm.     

Septal cholinergic mediation of hippocampal theta in the cat

The effects of intraseptally microinjected muscarinic (atropine sulfate, pirenzepine and gallamine) and nicotinic (hexamethonium) antagonists on spontaneous, sensory and electrically-induced hippocampal (HPC) theta EEG activity were investigated in the freely behaving cat. Administration of hexamethonium failed to elicit a detectable effect on HPC theta. Injections of atropine and pirenzepine abolished, whereas the injection of gallamine only reduced hippocampal theta. Moreover, a gradual recovery of theta amplitude and power was observed, while frequency recovered rapidly. Our data provide further evidence that the septal M1 and M2 muscarinic receptor subtypes mediate the HPC theta in this species. Intraseptal microinjection of cholinergic agonist (carbachol) produced almost a continuous HPC theta with increased amplitude and power. The contribution of the medial septal cholinergic projections to HPC theta frequency and amplitude was also discussed.     

Enhancement of afferent fiber activity in hippocampal slices

The potentiation of synaptic activity in the hippocampal formation is a well documented phenomenon. It has been suggested, however, that a recruitment of additional afferent fibers can contribute to such an increase in synaptic activity. The hypothesis of an enhancement in afferent fiber activity, therefore, was investigated with the in vitro hippocampal slice preparation. Isolated radiatum fiber compound action potentials were evoked with paired electrical stimuli of equal intensity and separated in time by 30–40 msec. Statistical comparisons between control and test evoked responses reveal an augmentation of the test responses in support of the hypothesis of an enhancement in afferent fiber activity.     

Lonf-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulase of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity if the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occuring theta rhythm may play a modulatory role in the induction of LTP.