Distinguishing characteristics of serotonin and non-serotonin-containing cells in the dorsal raphe nucleus: electrophysiological and immunohistochemical studies

Kirby, Lynn G.; Pernar, Luise I.M.; Valentino, Rita J.; Beck, Sheryl G.

doi:10.1016/s0306-4522(02)00584-5

Cited by 192 publications

(178 citation statements)

References 42 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…Twenty-one neurons were successfully labeled in 20 rats. These neurons were selected (see Materials and Methods) to be representatives of all major raphe cell groups reported in previous studies (10,13,14,18). ʈ Thus, the sample included both theta-on and theta-off units, i.e., cells activated or suppressed during theta and neurons with a wide range of firing rates (0.3-25 spikes per sec) and with a variety of spike waveforms.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, the firing of a large population (up to 55%) of raphe neurons in both anesthetized (9)(10)(11) and freely behaving rats (12) appeared phase-locked to hippocampal field potential oscillations at theta frequency. However, raphe neurons with theta-related firing were identified only by indirect electrophysiological criteria, whose reliability was questioned in recent studies by using combined cellular electrophysiology and immunohistochemistry (13)(14)(15). Thus, the important question of how the seemingly homogeneous population of serotonergic neurons is able to participate in the wide range of brain activity remains unanswered.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Kocsis

Varga

Dahan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

141

117

View full text Add to dashboard Cite

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 ...

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Kocsis

Varga

Dahan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

141

117

View full text Add to dashboard Cite

show abstract

“…For example, increased 5-HT 1A expression in the ventromedial DRN at the mid-rostral level would be expected to increase somatodendritic autoreceptor tone within this region, reducing serotonin release in terminal fields supplied by those neurons. Alternatively, the 5-HT 1A receptor has been reported on a small number of non-serotonergic neurons in the DRN (Kirby et al, 2003), especially in rostral DRN (Day et al, 2004). If the observed alterations in expression of this receptor reflected changes in this neuronal population, then intra-raphe circuits could also be modulating 5-HT independent of the autoreceptor activity.…”

mentioning

confidence: 99%

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

et al. 2007

View full text Add to dashboard Cite

Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1ng/hr), urocortin II (UCNII, 1ng/hr), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 minutes on each of two days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT 1A , 5-HT 1B , serotonin transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression were examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on reexposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT 1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT 1A , SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptDepression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States (Greenberg et al., 2003). They are often comorbid, and both are highly associated with chronic exposure to stress. Multiple lines of evidence suggest that chronic and inescapable stress produce long lasting effects on brain function and behavior that play a prominent role in the development, maintenance, and recurrence of both depression and a variety of anxiety disorders (Gulley and Nemeroff, 1993, Arborelius et al., 1999, Ressler and Nemeroff, 2000.Altered serotonin neurotransmission appears to be a central mechanism inducing both depressive (Maes and Meltzer, 1995) and anxiety disorders (Ressler and Nemeroff, 2000). The majority of serotonergic fibers to forebrain regions thought to be involved in mood and anxiety regulation arise from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) ...

show abstract

“…11,16 However, since the proof of an absence of expression is always subject to debate, we relied on the different methodologies utilized to increase the certitude of the estimate yielded by each technique alone. The occurrence of false negatives cannot be ruled out, and it is possible that in some cells the levels of 5-HT1A transcripts are extremely low and escape detection.…”

mentioning

confidence: 99%

“…This is consistent with immunohistochemical studies that showed a significant percentage of 5-HT cells that do not present immunoreactivity to a 5-HT1A antibody, indicating lack of protein expression. 11,16 In addition, electrophysiological studies where hyperpolarizing responses elicited by superfusion of a 5-HT1A agonist were assessed, found a considerable number of nonresponding identified serotonergic cells. 9,10,12,25 We hypothesized that while following the classic dogma to identify 5-HT neurons, many investigators have discarded data involving 5-HT1A-negative serotonergic neurons.…”

mentioning

confidence: 99%

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

Kiyasova

Bonnavion

Scotto-Lomassese

et al. 2012

ACS Chem. Neurosci.

View full text Add to dashboard Cite

5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/ R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA. In addition, we performed patch-clamp recordings followed by singlecell PCR in ePet1-eGFP mice. From 134 recorded 5-HT neurons located in the dorsal, lateral, and median raphe, we found lack of 5-HT1A mRNA expression in 22 cells, evenly distributed across raphe subfields. We compared the cellular characteristics of these neuronal types and found no difference in passive membrane properties and general excitability. However, when injected with large depolarizing current, 5-HT1A-negative neurons fired more action potentials, suggesting a lack of autoinhibitory action of local 5-HT release. Our results support the hypothesis that the 5-HT system is composed of subpopulations of serotonergic neurons with different capacity for adaptation.T he 5-hydroxytryptamine (5-HT, serotonin) neurotransmitter system has been strongly implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. 1,2 5-HT neurons are topographically organized in the hindbrain where distinct groups of neurons receive and send synaptic inputs from/to specific brain regions, suggesting that the neuronal activity of subpopulation of 5-HT neurons is under discrete spatiotemporal control. 3 Given the occurrence of neurochemically diverse neurons in the raphe nuclei, early studies proposed a series of features or "landmarks", common to all 5-HT neurons, that would help in the identification of putative 5-HT cells. 4−6 These included the regular firing of broad action potentials (clocklike activity) followed by a large afterhyperpolarization potential, high input resistance, and suppression of firing by 5-hydroxytryptamine receptor 1A (5-HT1A) agonists. 4−6 However, this dogma is progressively being questioned. Recent studies found that the electrophysiological characteristics of chemically identified 5-HT neurons in the raphe are more diverse than originally thought. 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. 10−12 Together these evidence call to re-evaluate the defi...

show abstract

Distinguishing characteristics of serotonin and non-serotonin-containing cells in the dorsal raphe nucleus: electrophysiological and immunohistochemical studies

Cited by 192 publications

References 42 publications

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

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

Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

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

Contact Info

Product

Resources

About