Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

Vestibular stimulation induced acetylcholine release in the hippocampus, and acetylcholine is known to facilitate long-term potentiation (LTP) in the hippocampus. Thus, we hypothesize that vestibular stimulation enhances LTP in CA1 in freely behaving rats, and this enhancement depends on the activation of septohippocampal cholinergic neurons. Field excitatory postsynaptic potentials were recorded in CA1 area of behaving rats following stimulation of the basal dendritic afferents. LTP was induced by a single stimulation train (100 pulses at 200 Hz) during passive whole-body rotation or during awakeimmobility. LTP induced during rotation was significantly larger than that induced during immobility. Pretreatment with cholinergic antagonist atropine sulfate (50 mg/kg i.p.) abolished the facilitation of LTP during rotation as compared to immobility. Selective lesion of cholinergic cells in the medial septum (MS) with 192 IgG-saporin (0.49 microg in 1.4 microl) also abolished the difference in LTP induced during rotation and immobility, which was found in sham-lesion rats. 192 IgG-saporin lesioned rats, as compared to sham-lesion rats, revealed a depletion of MS cells immunopositive to choline acetyltransferase and paling of acetylcholinesterase staining in the hippocampus, without significant change in the number of parvalbumin-immunopositive cells. We conclude that enhancement of LTP during vestibular stimulation is mediated by the activation of cholinergic septohippocampal cells. This is the first direct evidence that vestibular stimulation facilitates hippocampal synaptic plasticity via a cholinergic input

Lesion of cholinergic neurons in nucleus basalis enhances response to general anesthetics

Acetylcholine in the brain has been associated with consciousness and general anesthesia effects. We tested the hypothesis that the integrity of the nucleus basalis magnocellularis (NBM) affects the response to general anesthetics. Cholinergic neurons in NBM were selectively lesioned by bilateral infusion of 192IgG-saporin in adult, male Long–Evans rats, and control rats were infused with saline. Depletion of choline-acetyltransferase (ChAT)-immunoreactive cells in the NBM and decrease in optical density of acetylcholinesterase (AChE) staining in the frontal and visual cortices confirmed a significant decrease in NBM cholinergic neurons in lesioned as compared to control rats. AChE staining in the hippocampus and ChAT-positive neurons in the medial septum–vertical limb of the diagonal band were not different between lesioned and control rats. When a general anesthetic was administered, lesioned compared to control rats showed significantly longer duration of loss of righting reflex (LORR) after propofol (5 or 10 mg/kg i.v.), pentobarbital (20 or 40 mg/kg i.p.) but not halothane (2%). However, the behavioral excitation, as indicated by horizontal movements, induced by halothane was reduced in lesioned as compared to control rats. Reversible inactivation of NBM with GABAA receptor agonist muscimol increased slow waves in the neocortex during awake immobility, and prolonged the duration of LORR and loss of tail-pinch response after propofol, pentobarbital and halothane. In summary, lesion of NBM cholinergic neurons or inactivation of the NBM prolonged the LORR response to general anesthetic drugs

Disruption of Hippocampal Multisynaptic Networks by General Anesthetics.

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function. METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal). RESULTS: Monosynaptic population excitatory postsynaptic potentials at the basal and apical dendrites of CA1 were significantly decreased at greater than or equal to 0.25% (n = 4) and greater than or equal to 1.0% (n = 6) isoflurane, respectively. The perforant path evoked multisynaptic response at CA1 was decreased by ~50% at greater than or equal to 0.25% isoflurane (n = 5). A decreased population excitatory postsynaptic potential was accompanied by increased paired-pulse facilitation. Population spike amplitude in relation to apical dendritic population excitatory postsynaptic potential was not significantly altered by isoflurane. Spontaneous hippocampal local field potential at 0.8 to 300 Hz was dose-dependently suppressed by isoflurane (n = 6), with local field potential power in the 50- to 150-Hz band showing the highest decrease with isoflurane dose, commensurate with the decrease in trisynaptic CA1 response. Low-dose pentobarbital (n = 7) administration decreased the perforant path evoked trisynaptic CA1 response and hippocampal local field potentials at 78 to 125 Hz. CONCLUSIONS: Hippocampal networks are sensitive to low doses of isoflurane and pentobarbital, possibly through both glutamatergic and γ-aminobutyric acid-mediated transmission. Network disruption could help explain the impairment of hippocampal-dependent cognitive functions with low-dose anesthetic

Medial septal cholinergic neurons modulate isoflurane anesthesia.

BACKGROUND: Cholinergic drugs are known to modulate the response of general anesthesia. However, the sensitivity of isoflurane or other volatile anesthetics after selective lesion of septal cholinergic neurons that project to the hippocampus is not known. METHODS: Male Long Evans rats had 192 immunoglobulin G-saporin infused into the medial septum (n = 10), in order to selectively lesion cholinergic neurons, whereas control, sham-lesioned rats were infused with saline (n = 12). Two weeks after septal infusion, the hypnotic properties of isoflurane and ketamine were measured using a behavioral endpoint of loss of righting reflex (LORR). Septal lesion was assessed by counting choline acetyltransferase-immunoreactive cells and parvalbumin-immunoreactive cells. RESULTS: Rats with 192 immunoglobulin G-saporin lesion, as compared with control rats with sham lesion, showed a 85% decrease in choline acetyltransferase-immunoreactive, but not parvalbumin-immunoreactive, neurons in the medial septal area. Lesioned as compared with control rats showed increased isoflurane sensitivity, characterized by a leftward shift of the graph plotting cumulative LORR percent with isoflurane dose. However, lesioned and control rats were not different in their LORR sensitivity to ketamine. When administered with 1.375% isoflurane, LORR induction time was shorter, whereas emergence time was longer, in lesioned as compared with control rats. Hippocampal 62-100 Hz gamma power in the electroencephalogram decreased with isoflurane dose, with a decrease that was greater in lesioned (n = 5) than control rats (n = 5). CONCLUSIONS: These findings suggest a role of the septal cholinergic neurons in modulating the sensitivity to isoflurane anesthesia, which affects both induction and emergence. The sensitivity of hippocampal gamma power to isoflurane appears to indicate anesthesia (LORR) sensitivity

Positive allosteric modulator of GABAB receptor alters behavioral effects but not afterdischarge progression induced by partial hippocampal kindling.

Hippocampal seizures decreased the function of GABAB receptors, which may further increase seizure susceptibility and contribute to development of schizophrenia-like behaviors. Recent literature indicates that GABAB receptor agonist may normalize schizophrenia-like behaviors and prevent drug-induced behavioral sensitization. We hypothesized that positive modulation of GABAB receptor function during seizure induction will reduce seizure-induced schizophrenia-like behaviors. Using a partial hippocampal kindling model, afterdischarges were induced after injection of saline or dimethyl sulfoxide (vehicle-kindled rats), or a GABAB receptor positive allosteric modulator CGP7930, at 1 mg/kg i.p. (CGP1-kindled) or 5 mg/kg i.p. (CGP5-kindled). The increase in the primary afterdischarge duration during kindling was not different among the groups. However, the CGP5-kindled group showed a lower afterdischarge starting frequency as compared to vehicle-kindled or CGP1-kindled groups. Partial hippocampal kindling (21 afterdischarges) resulted in decreased prepulse inhibition and decreased gating of hippocampal auditory evoked potentials in vehicle-kindled and CGP1-kindled rats, as compared to saline-injected non-kindled rats, recorded 3-4 days after the last afterdischarge. However, CGP5-kindled rats showed normal prepulse inhibition and hippocampal auditory gating (compared to non-kindled rats), which was significantly higher than the respective measure in vehicle-kindled rats. CGP5-kindled group also showed methamphetamine-induced locomotion that was significant lower than the vehicle-kindled or CGP1-kindled group, but slightly higher than the saline-injected non-kindled rats. In conclusion, this study provides original data that a GABAB receptor positive allosteric modulator could therapeutically prevent or normalize some seizure-induced behavioral disruptions in a model of temporal lobe epilepsy

Resting state functional network disruptions in a kainic acid model of temporal lobe epilepsy.

We studied the graph topological properties of brain networks derived from resting-state functional magnetic resonance imaging in a kainic acid induced model of temporal lobe epilepsy (TLE) in rats. Functional connectivity was determined by temporal correlation of the resting-state Blood Oxygen Level Dependent (BOLD) signals between two brain regions during 1.5% and 2% isoflurane, and analyzed as networks in epileptic and control rats. Graph theoretical analysis revealed a significant increase in functional connectivity between brain areas in epileptic than control rats, and the connected brain areas could be categorized as a limbic network and a default mode network (DMN). The limbic network includes the hippocampus, amygdala, piriform cortex, nucleus accumbens, and mediodorsal thalamus, whereas DMN involves the medial prefrontal cortex, anterior and posterior cingulate cortex, auditory and temporal association cortex, and posterior parietal cortex. The TLE model manifested a higher clustering coefficient, increased global and local efficiency, and increased small-worldness as compared to controls, despite having a similar characteristic path length. These results suggest extensive disruptions in the functional brain networks, which may be the basis of altered cognitive, emotional and psychiatric symptoms in TLE

Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo.

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing-generating synaptic excitation before a spike-results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of -10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60-120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of -10 ms to 0 ms but no LTD at ES intervals of -20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus

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