Sensory Responses of Neurons in the Medial Septal Area in Conditions of Modulation of Theta Activity Using the Alpha-2-Adrenoreceptor Agonist Clonidine

Abstract

Our previous studies on conscious rabbits showed that administration of the alpha-2-adrenoreceptor agonist clonidine induces dose-dependent changes in theta oscillations in the septohippocampal system. Low doses of clonidine suppressed theta activity, while high doses produced significant potentiation. It was suggested that the different effects of clonidine might be associated with differences in the sensitivities of pre- and postsynaptic alpha-2-adrenoreceptors to clonidine, this agent being a pure agonist of noradrenaline when used at high doses. It was suggested that functional synergism occurs between the activatory reticular formation and the noradrenergic system of the locus ceruleus in controlling the theta rhythm. The present study was performed to identify the nature of the responses of sensory neurons in the medial septal region in conditions of alterations in the magnitude of the theta rhythm induced by different doses of clonidine. Low and high doses of the agonist given bilaterally into the lateral ventricles were found to have different effects on the sensory responses of neurons in the medial septal region. Injection of small clonidine doses (0.5 microg in 5 microl into each lateral ventricle), which decrease theta activity, was found to lead to weakening of activatory processes and enhancement of inhibitory processes in the medial septal region. The number of activatory responses decreased significantly and persisting responses were significantly weakened; inhibitory responses, conversely, were seen more frequently and were significantly more marked. Administration of high clonidine doses (5 microg in 5 microl), which produce sharp increases in theta oscillations, led to significant reductions in the reactivity of cells in the medial septal region to sensory stimuli (from 76.8% in controls to 45% after clonidine), regardless of the nature of the initial responses. Persisting activatory and inhibitory responses were in most cases less marked than the initial responses. These results suggest that alpha-2-adrenoreceptors are involved in controlling the sensory reactivity of neurons in the medial septal region. The impairment of the normal processing of sensory stimuli seen during the continuous generation of rhythmic activity provoked by injection of large clonidine doses supports the role of the theta rhythm in the septohippocampal system as an active filter during the processing and recording of information.

Theta Oscillations and Reactivity of Hippocampal Stratum Oriens Neurons

“…The sensory and electrical stimulations were applied in the control and after the artificial adjustments of theta rhythm. An increase in the hippocampal theta rhythm was achieved by three different methods: (1) an intravenous injection of the acetylcholinesterase inhibitor physostigmine [43,46], (2) an intraventricular injection of the alpha2 adrenoceptor agonist clonidine [23,24], or (3) an injection of the local anesthetic lidocaine into the median raphe nucleus [22,41] (see section "Strong Increase of Theta Rhythm Blocks the Majority of Responses"). In the same or separate experiments, the theta was blocked by three methods: (1) an intravenous injection of the antagonist of cholinergic muscarinic receptors scopolamine [43,46], (2) an injection of lidocaine into the medial septal-diagonal band region (MS) [47], or (3) an intraventricular injection of the alpha2 adrenoceptor antagonist idazoxan [23] (see section "Theta Rhythm Blockade Preserves and Enhances the Responses to the Input Stimulation").…”

“…The data presented in the review are based on the analysis of the activity of 185 putative theta interneurons of CA1-CA3 stratum oriens that exhibited theta modulation. These theta cells were selected from a pool of hippocampal neurons recorded in 20 rabbits [22,23,24,43,44,45,46,47].…”

“…One of the methods of theta increase was an intravenous injection of the acetylcholinesterase inhibitor physostigmine (0.1 mg/kg), a functional agonist of acetylcholine, which increased theta rhythm in the hippocampal EEG to 195  82% of control values [43]. Another, more effective, way to theta elevation was an intraventricular injection of the alpha2 adrenoceptor agonist clonidine (5 μg dissolved in 5 μl), which evidently increased the adrenergic transmission in the brain [24]. Clonidine increased the hippocampal theta rhythm to 390  89% of control.…”

“…The hypothesis was advanced that the neuronal theta rhythmicity determines the signal selection at the level of the hippocampus. The experimental data on the responses of hippocampal cells to sensory and electrical stimulation under control conditions and during artificially increased or blocked theta rhythm are reviewed here with emphasis on the responses of putative interneurons of the CA1-СА3 hippocampal stratum oriens [22,23,24,43,44,45,46,47]. A subset of these cells directly contributes to the theta rhythm generation; they are tuned to operate at theta frequencies [13,14,25], and the disruption of their spiking is accompanied by a loss of both the field theta and IPSP trains at the theta frequency [12].…”

Study of electrical activity of subcortical structures of the brain after destruction of the dorsal amygdalofugal pathway

“…One of the main structure of the limbic system is hippocampus for which a peculiar (special, own)form of bioelectric activity -theta rhythm is specific. According to the literary data necessary afferent flow(flux) is provided by ascending systems, its transformation into rhythmic activity occurs on a special hippocampal relay that is considered as a pacemaker of hippocampal thetarhythm [1,2,3,4]. Ascending fibres as a part of the medialanterior cerebral bundle enter the medial septal nucleus from the subcortical brain structures which play an important role in the mechanisms of formation of rhythmic hippocampal activity [5,6,7,8,9].…”