Engin E, Stellbrink J, Treit D, Dickson CT
Neuroscience 2008 Dec;157(3):666-76
Somatostatin (SST) is a cyclic polypeptide that inhibits the release of a variety of regulatory hormones (e.g. growth hormone, insulin, glucagon, thyrotropin). Moreover, SST is widely distributed within the CNS, acting both as a neurotransmitter and as a neuromodulator of other neurotransmitter systems. However, despite its extensive expression in limbic areas, and its co-localization with GABA, a neurotransmitter previously implicated in emotion, the effects of SST on anxiety and depression have not been investigated. By performing intraventricular infusions in rats we demonstrate, for the first time, that SST has anxiolytic- and antidepressant-like effects in the elevated plus-maze and forced swim test, respectively. In addition, by performing local field potential recordings of hippocampal theta activity evoked by reticular stimulation in urethane-anesthetized rats we also show that SST application suppresses the frequency of theta in a similar fashion to diazepam. This neurophysiological signature, common to all classes of anxiolytic drugs (i.e. benzodiazepines, selective 5-HT reuptake inhibitors, 5-HT1A agonists) provides strong converging evidence for the anxiolytic-like characteristics of SST. Our pharmacological antagonism experiments with bicuculline further suggest that the anxiolytic effect of SST may be attributable to the interaction of SST with GABA, whereas the antidepressant-like effect of SST may be GABA-independent. In addition to contributing to the current understanding of the role of neuropeptides in mood and emotion, these findings support a clinical role for SST (or its analogues) in the treatment of anxiety and depression.
Saraga F, Balena T, Wolansky T, Dickson CT, Woodin MA
Neuroscience 2008 Jul;155(1):64-75
Spike-timing modifies the efficacy of both excitatory and inhibitory synapses onto CA1 pyramidal neurons in the rodent hippocampus. Repetitively spiking the presynaptic neuron before the postsynaptic neuron induces inhibitory synaptic plasticity, which results in a depolarization of the reversal potential for GABA (E(GABA)). Our goal was to determine how inhibitory synaptic plasticity regulates CA1 pyramidal neuron spiking in the rat hippocampus. We demonstrate electrophysiologically that depolarizing E(GABA) by 24.7 mV increased the spontaneous action potential firing frequency of cultured hippocampal neurons 254% from 0.12+/-0.07 Hz to 0.44+/-0.13 Hz (n=11; P<0.05). Next we used a single compartment model of a CA1 pyramidal neuron to explore in detail how inhibitory synaptic plasticity of feedforward and feedback inhibition regulates the generation of action potentials, spike latency, and the minimum excitatory conductance required to generate an action potential; plasticity was modeled as a depolarization of E(GABA), which effectively weakens inhibition. Depolarization of E(GABA) at feedforward and feedback inhibitory synapses decreased the latency to the 1st spike by 2.27 ms, which was greater that the sum of the decreases produced by depolarizing E(GABA) at feedforward (0.85 ms) or feedback inhibitory synapses (0.02 ms) alone. In response to a train of synaptic inputs, depolarizing E(GABA) decreased the inter-spike interval and increased the number of output spikes in a frequency dependent manner, improving the reliability of input-output transmission. Moreover, a depolarizing shift in E(GABA) at feedforward and feedback synapses triggered by spike trains recorded from CA1 pyramidal layer neurons during field theta from anesthetized rats, significantly increased spiking on the up- and down-strokes of the first half of the theta rhythm (P<0.05), without changing the preferred phase of firing (P=0.783). This study provides the first explanation of how depolarizing E(GABA) affects pyramidal cell output within the hippocampus.
Jackson J, Dickson CT, Bland BH
J. Neurophysiol. 2008 Jun;99(6):3009-26
Evidence has accumulated suggesting that the median raphe (MR) mediates hippocampal theta desynchronization. However, few studies have evaluated theta-related neural circuitry during MR manipulation. In urethane-anesthetized rats, we investigated the effects of MR stimulation on hippocampal field and cell activity using high-frequency (100 Hz), theta burst (TBS), and slow-frequency electrical stimulation (0.5 Hz). We demonstrated that high-frequency stimulation of the MR did not elicit deactivated patterns in the forebrain, but rather elicited low-voltage activity in the neocortex and small-amplitude irregular activity (SIA) in the hippocampus. Both hippocampal phasic theta-on and -off cells were inhibited by high-frequency MR stimulation, although MR stimulation failed to affect cells that had neither state or phase relationships with theta field activity. TBS of the MR-induced theta field activity phase locked to the stimulation. Slow-frequency stimulation elicited a state-dependent reset of theta phase through a short-latency inhibition (5 ms) in phasic theta-on cells. Subpopulations of phasic theta-on cells responded in either oscillatory or nonoscillatory patterns to MR pulses, depending on their intraburst interval. off cells exhibited a state-dependent modulation of cell firing occurring preferentially during nontheta. The magnitude of MR-induced reset varied as a function of the phase of the theta oscillation when the pulse was administered. Therefore high-frequency stimulation of the MR appears to disrupt hippocampal theta through a state-dependent, short-latency inhibition of rhythmic cell populations in the hippocampus functioning to switch theta oscillations to an activated SIA field state.
Schall KP, Kerber J, Dickson CT
J. Neurophysiol. 2008 Feb;99(2):888-99
Coordinated patterns of state-dependent synchronized oscillatory activity have been suggested to play differential roles in both the encoding and consolidation phases of hippocampal-dependent memories. Previous studies have concentrated on the mutually exclusive patterns of theta and sharp-wave/ripple activity because these were thought to be the only collective oscillatory patterns expressed in the hippocampus. Recently we (and others) have described a novel rhythmic activity expressed during anesthesia and deep sleep, the hippocampal slow oscillation (SO). In an attempt to describe the differential effects of theta and the SO on processing in the hippocampal circuit, we performed evoked potential analysis of two major pathways (the commissural and perforant) in urethan-anesthetized rats across spontaneously expressed theta and SO states. We show that synaptic excitability was significantly enhanced in all pathways during the SO as compared with theta with the exception of the medial perforant path to the dentate gyrus, which showed greater excitability during theta. Furthermore, within each ongoing rhythm, there was a phase-dependent modulation of synaptic excitability. This occurred across all sites and similarly favored the falling phase (positive to negative) of both theta and the SO. Differential effects on the input, processing, and output circuitries of the hippocampus across mutually exclusive coordinated oscillatory patterns expressed during different states may be relevant for the staging of memory processes in the medial temporal lobe.
Ma L, Alonso A, Dickson CT
Neural Plast. 2008;2008:814815
The entorhinal cortex (EC) is a nodal and independent mnemonic element of the medial temporal lobe memory circuit as it forms a bidirectional interface between the neocortex and hippocampus. Within the EC, intra- and inter-lamellar associational connections occur via horizontal and columnar projections, respectively. We undertook a comparative study of these two inputs as they converge upon EC layer II cells using whole-cell patch techniques in an adult rat EC horizontal slice preparation in which the deepest layers (V-VI) had been dissected out. Electrical stimulation of layers I and III during GABA blockade allowed us to study excitatory synaptic properties and plasticity in the horizontal and columnar fibre systems, respectively. Both pathways exhibited AMPA- and NMDA-receptor mediated transmission and both exhibited long-term potentiation (LTP) after high-frequency (tetanic) stimulation. LTP in the horizontal, but not in the columnar pathway, was blocked by NMDA receptor antagonism. Intriguingly, LTP in both appeared to be mediated by post synaptic increases in Ca2+ that may be coupled to differing second messenger pathways. Thus, the superficial excitatory horizontal and columnar associative pathways to layer II have divergent mechanisms for LTP which may endow the EC with even more complex and dynamic processing characteristics than previously thought.
Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT
PLoS ONE 2008;3(4):e2004
BACKGROUND: Although the induction of behavioural unconsciousness during sleep and general anaesthesia has been shown to involve overlapping brain mechanisms, sleep involves cyclic fluctuations between different brain states known as active (paradoxical or rapid eye movement: REM) and quiet (slow-wave or non-REM: nREM) stages whereas commonly used general anaesthetics induce a unitary slow-wave brain state.
METHODOLOGY/PRINCIPAL FINDINGS: Long-duration, multi-site forebrain field recordings were performed in urethane-anaesthetized rats. A spontaneous and rhythmic alternation of brain state between activated and deactivated electroencephalographic (EEG) patterns was observed. Individual states and their transitions resembled the REM/nREM cycle of natural sleep in their EEG components, evolution, and time frame ( approximately 11 minute period). Other physiological variables such as muscular tone, respiration rate, and cardiac frequency also covaried with forebrain state in a manner identical to sleep. The brain mechanisms of state alternations under urethane also closely overlapped those of natural sleep in their sensitivity to cholinergic pharmacological agents and dependence upon activity in the basal forebrain nuclei that are the major source of forebrain acetylcholine. Lastly, stimulation of brainstem regions thought to pace state alternations in sleep transiently disrupted state alternations under urethane.
CONCLUSIONS/SIGNIFICANCE: Our results suggest that urethane promotes a condition of behavioural unconsciousness that closely mimics the full spectrum of natural sleep. The use of urethane anaesthesia as a model system will facilitate mechanistic studies into sleep-like brain states and their alternations. In addition, it could also be exploited as a tool for the discovery of new molecular targets that are designed to promote sleep without compromising state alternations.