Serotonergic neuron diversity: Identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm

Abstract

The serotonergic system plays a key role in the regulation of brain states, and many of the known features of serotonergic neurons appear to match this function. Midbrain raphe nuclei provide a diffuse projection to all regions of the forebrain, and raphe neurons exhibit a slow metronome-like activity that sets the ambient levels of serotonin across the sleep-wake cycle. Serotonergic cells have also been implicated, however, in a variety of more specific functions that can hardly be related to their low-rate monotonous patterns of discharges. The amazing variety of serotonergic receptors and their type-specific distribution on cortical neurons also raise the possibility of a more intimate coordination between the activity of serotonergic neurons and their target cortical circuits. Here we report an unexpected diversity in the behavior of immunohistochemically identified serotonergic neurons. Two outstanding subpopulations were identified by using the in vivo juxtacellular recording and labeling technique. The first subpopulation of serotonergic cells exhibited the classic clock-like activity with no apparent short timescale interaction with the hippocampal electroencephalogram. The other subpopulation discharged action potentials that were phase-locked to the hippocampal theta rhythm, the oscillatory pattern associated with acquisition of information and memory formation. These results indicate that the ascending serotonergic system comprises cells involved in complex information processing beyond the regulation of state transitions. The heterogeneity of serotonergic neuron behavior can also help to explain the complexity of symptoms associated with serotonergic dysfunction.hippocampus ͉ juxtacellular labeling ͉ midbrain raphe ͉ neuronal oscillations T he serotonergic system is a primary target of psychotherapy that stresses the importance of serotonin in normal and abnormal brain functioning. Serotonergic neurons of the midbrain raphe have been implicated in the control of affective and cognitive functions and in modulating the neural activities of networks across the sleep-wake cycle. Behaviorally related oscillations in the theta frequency range (4-8 Hz), which are most prominent in the hippocampus (1), are known to synchronize neuronal activity in a number of forebrain structures involved in these functions (2-4). Hippocampal theta oscillations occur selectively during exploratory behaviors and paradoxical sleep, whereas large-amplitude irregular activity is associated with quiet waking, consummatory behaviors, and slow-wave sleep (5, 6). As in sleep, hippocampal activity spontaneously alternates between theta and nontheta states under urethane anesthesia.The majority of putative serotonergic neurons have been reported to be most active during waking, to decrease their firing rate during slow-wave sleep, and to cease firing during paradoxical sleep (7). ʈ The silencing of serotonergic cells during paradoxical sleep is currently considered an important regulatory signal that contributes to the maintenance of ...

Midbrain Raphe Stimulation Improves Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury

“…The upper bound of the normal firing range for serotonergic neurons is about 8 Hz, whereas non-serotonergic neurons in raphe nuclei can fire at higher frequencies. 37,38 Thus, the serotonergic neurons may not have been able to follow the 24 Hz stimulation during an entire 5-min train. Low-frequency MR stimulation (0.5 Hz) but not high frequency (100 Hz) reportedly causes a statedependent reset of phase of the theta rhythm, 47 which is thought to increase stimulus-processing in hippocampal networks.…”

“…35,36 A fairly low stimulation frequency of 8 Hz was used in most treated groups, which was just at the higher limit of the range of firing of midbrain serotonergic neurons. 37,38 Pauses of 5 min were alternated with 5-min bouts of stimulation, allowing recovery of serotonin release mechanisms, as suggested to be Figure 3. DR, dorsal raphe; MR, median raphe.…”

Activation of Dorsal Raphe Serotonin Neurons Underlies Waiting for Delayed Rewards

“…2 A). To identify serotonin neurons, we used three criteria: wide spike waveform, low tonic firing rate, and suppression by 5-HT 1A autoreceptor activation (Aghajanian et al, 1978;Vandermaelen and Aghajanian, 1983), although some exceptions have been recently reported, such as slow-firing non-5-HT neurons (Allers and Sharp, 2003), theta rhythmic firing of 5-HT neurons (Kocsis et al, 2006), and expression of 5-HT 1A receptors in a subset of non-5-HT neurons (Kirby et al, 2003;Marinelli et al, 2004). We tested the responses of 48 neurons to systemic injection of the 5-HT 1A receptor agonist 8-OH-DPAT and observed suppression of the firing rates of 33 neurons (Fig.…”

A Subpopulation of Serotonergic Neurons That Do Not Express the 5-HT1A Autoreceptor

“…Using juxtacellular labeling techniques, it was found that, besides the population of slow-firing clocklike cells, in vivo discharge of 5-HT neurons also includes subpopulations of fastfiring and bursting neurons. 7,8 Moreover, in vitro patch-clamp studies conducted in brain slices demonstrated a high degree of variability in the passive and active membrane properties of 5-HT neurons. 9,10 Finally, anatomical and electrophysiological studies showed that 5-HT1A receptors are not only expressed in 5-HT neurons, but also in other neuronal classes in the raphe nuclei.…”

“…However, our results showed that given the same excitatory input, cells that do not express 5-HT1A reach higher discharge frequencies. It is then possible, that these cells could correspond to the subpopulation of fastfiring, 7,30 or even bursting 5-HT neurons. 28,31 In conclusion, we showed here that, despite the classic dogma, not all 5-HT neurons in the mouse raphe express the 5-HT1A autoreceptor mRNA, and that 5-HT cells lacking 5-HT1A mRNA are prone to fire at higher discharge frequencies.…”