GABAergic control of the ascending input from the median raphe nucleus to the limbic system - PubMed (original) (raw)

Comparative Study

. 2005 Oct;94(4):2561-74.

doi: 10.1152/jn.00379.2005. Epub 2005 Jun 8.

Affiliations

Comparative Study

GABAergic control of the ascending input from the median raphe nucleus to the limbic system

Shaomin Li et al. J Neurophysiol. 2005 Oct.

Abstract

The median raphe nucleus (MRN) is the primary source of serotonergic afferents to the limbic system that are generally considered to suppress hippocampal theta oscillations. GABA receptors are expressed in the MRN by serotonergic and nonserotonergic cells, including GABAergic and glutamatergic neurons. This study investigated the mechanisms by which the fluctuating GABA tone in the MRN leads to induction or suppression of hippocampal theta rhythm. We found that MRN application of the GABA(A) agonist muscimol (0.05-1.0 mM) or GABA(B) agonist baclofen (0.2 mM) by reverse microdialysis had strong theta promoting effects. The GABA(A) antagonist bicuculline infused in low concentrations (0.1, 0.2 mM) eliminated theta rhythm. A short period of theta activity of higher than normal frequency preceded hippocampal desynchronization in 46% of rats. Bicuculline in larger concentrations (0.5, 1.0, 2.0 mM) resulted in a biphasic response of an initial short (<10 min) hippocampal desynchronization followed by stable theta rhythm that lasted as long as the infusion continued. The frequency and amplitude of theta waves were higher than in control recordings and the oscillations showed a conspicuous intermittent character. Hippocampal theta rhythm elicited by MRN administration of bicuculline could be completely (0.5 mM bicuculline) or partially (1.0 mM bicuculline) blocked by simultaneous infusion of the GABA(B) antagonist CGP35348. Our findings suggest that the GABAergic network may have two opposing functions in the MRN: relieving the theta-generators from serotonergic inhibition and regulating the activity of a theta-promoting circuitry by the fluctuating GABA tone. The two mechanisms may be involved in different functions.

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Figures

Figure 1

Figure 1

Location of the microdialysis probe in the median raphe nucleus. A and B. Microphotographs show the track of the probe in 2 coronal section at separated by 0.6 mm. C. Schematic drawing of the location of the microdialysis probe inserted into the median raphe nucleus under a 24 deg angle in dorsocaudal to ventrolateral direction, in the sagital plane. Vertical markers at −7.2 and −8.7 indicate the borders of the MRN. The dialysis membrane was in the anterior, “bulky” part of the MRN. D. Location of the probes at coronal section −7.9 mm from Bregma (D3) (Paxinos and Watson 2005) and the tip of the probes in different experiments (D1 and D2). Calibration in A and B: 1 mm.

Figure 2

Figure 2

Effect of injections of GABA receptor agonists in the median raphe nucleus. A. Sample hippocampal EEG recordings during control non-theta (a); and control theta epochs (b); during muscimol (0.1mM) injection (c); and 20 min after perfusion with muscimol halted (d). B. Power spectra of hippocampal EEG (4 s segments) during perfusion of GABAA agonist (a, Muscimol 0.1 mM, red line) and GABAB agonist (b, Baclofen 0.2 mM, red line). Black lines show control ACSF perfusion. C. time-frequency contour plot of hippocampal EEG power spectra before and during drug administration (a, Muscimol 0.1 mM and b, Baclofen 0.2 mM). White arrow indicates start of drug perfusion. Calibration: 2 mV, 1 sec (A).

Figure 3

Figure 3

Effect of GABAA receptor antagonist injection in median raphe nucleus. A. Specimen recordings of hippocampal non-theta (upper trace) and theta (lower trace) EEG. B. power spectra of 4 s theta and non-theta EEG segments. C. Time-frequency contour plot of hippocampal EEG power spectra before (control) and during microdialysis perfusion of 0.2 mM and 1.0 mM Bicuculline (start at 10 min).

Figure 4

Figure 4

Effect of GABA receptor blockade in the MRN on the occurrence of hippocampal theta rhythm, and its frequency and amplitude. A. Percent time spent in the theta state during 20 min segments immediately before and 20 min after the start of drug injection. Note large decrease in standard error after Muscimol, Baclofen, and BIC injections. B. Theta frequency before, during (20 min), and at the end (60 min) of infusion of GABA antagonists. C. Theta power before, during (20 min), and at the end (60 min) of infusion of GABA antagonists. Error bars mark standard error of the mean.

Figure 5

Figure 5

Effect of GABAA receptor agonists (A) and antagonists (B) administered in brainstem structures adjacent to MRN. Time-frequency contour plot of hippocampal EEG spectra before and during microdialysis perfusion of 0.5 mM Muscimol (A, start marked by white arrow) and 0.5 mM Bicuculline (B, start at 0 min).

Figure 6

Figure 6

Theta acceleration during infusion of GABAA receptor blockers in the MRN. A. Early theta acceleration in a rat receiving 0.2 mM BIC (injection started at 0 min). Note rapid change in theta frequency at the beginning of infusion. a and b. specimen EEG segments before and after theta acceleration. B. Time-frequency contour plot of EEG power spectra during infusion of 1.0 mM BIC. Note rapid increase of theta frequency at the beginning and slow increment after 30–40 min of drug administration.

Figure 7

Figure 7

Modulation of theta amplitude during infusion of GABAA receptor blocker in the MRN. A. EEG traces before (ctrl) and during BIC infusion. Traces in b were passed through a digital high pass filter (Butterworth, order 10) to eliminate slow baseline fluctuations. B. Strong amplitude modulation in another experiment with slow theta (theta frequency: 4.2 Hz, modulation frequency: 1.8 Hz). C. Time-frequency contour plot of hippocampal EEG. Note increase in theta frequency from 5Hz in control to 5.8 Hz 15–20 min after start of drug administration. A low frequency component (~1.1 Hz) also appeared in the power spectra about the same time.

Figure 8

Figure 8

Fast theta bursts in the hippocampus during infusion of GABAA receptor blocker in the MRN. A. Time frequency contour plot shows three frequency components in an experiment at the end of the 1 hr long injection of 1.0 mM BIC. Note a fast ~8 Hz component in addition to theta (4–5 Hz) and delta (1–2 Hz) peaks. Traces on the right show a segment of the original EEG (a; 1–70 Hz); and its low-pass (b; <5Hz) and high-pass filtered (c; >5 Hz) components. B. Regular ~4Hz theta rhythm during control (left panel) and Fast theta bursts (~6 Hz; right panel) in a different rat receiving 0.5 mM BIC. Contour plot shows regular (~4 Hz) theta in control; a, b, and c as above.

Figure 9

Figure 9

Effect of total GABA blockade (GABAA and GABAB) of the MRN on hippocampal theta rhythm. A. Time frequency contour plot of hippocampal EEG before and during coadministration of 0.5 mM BIC and 2.5 mM CGP35348. B. Same for another rat receiving 1 mM BIC and 5 mM CGP35348. The occurrence of theta segments in the EEG was highest in this experiment. Note lack of constant theta observed during 1 mM BIC (compare with Figs 3C, 4B, 5A).

Figure 10

Figure 10

Minimal circuit model of the GABAergic control of MRN limbic forebrain projections involved in the control of hippocampal theta rhythm. During non-theta states the MRN output is dominated by serotonergic activity. At the onset of theta, incoming excitatory drive increases GABAergic tone and suppresses serotonergic cells via GABAA- and GABAB-Rs (Varga et al. 2002) releasing the theta-generating circuitry from the serotonergic inhibition. The MRN 5-HT-GABA system is stabilized by feedback through 5-HT1A autoreceptors and 5-HT2-Rs on GABAergic neurons (Liu et al. 2000). GABAB-Rs are recruited by increased GABAergic tone (Nitz and Siegel 1997) and synchronized firing of GABAergic cells (Kocsis and Vertes 1992). Besides the inhibition of serotonergic neurons putative glutamatergic (Kiss et al. 2002), theta-promoting circuits are activated which can also be the targets of GABAergic inhibition. Thus, the GABAergic network may have two seemingly opposing function in the MRN: relieving the theta-generators from the serotonergic inhibition and regulating the activity in the theta-promoting circuitry by the fluctuating GABAergic tone.

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References

    1. Abellan MT, Jolas T, Aghajanian GK, Artigas F. Dual control of dorsal raphe serotonergic neurons by GABAB receptors. Electrophysiological and microdialysis studies. Synapse. 2000;36:21–34. - PubMed
    1. Allers KA, Sharp T. Neurochemical and anatomical identification of fast- and slow-firing neurones in the rat dorsal raphe nucleus using juxtacellular labelling methods in vivo. Neuroscience. 2003;122:193–204. - PubMed
    1. Assaf SY, Miller JJ. The role of a raphe-serotonin system in the control of septal unit activity and hippocampal desynchronization. Neuroscience. 1978;3:539–550. - PubMed
    1. Bagdy E, Kiraly I, Harsing L. Reciprocal innervation between serotonergic and GABAergic neurons in raphe nuclei of the rat. Neurochem Res. 2000;25:1465–1473. - PubMed
    1. Boehnke SE, Rasmusson DD. Time course and effective spread of lidocaine and tetrodotoxin delivered via microdialysis: ene electrophysiological study in cerebral cortex. J Neurosci Methods. 2001;105:133–141. - PubMed

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