Atypical, but Not Typical, Antipsychotic Drugs Reduce Hypersynchronized Prefrontal-Hippocampal Circuits during Psychosis-Like States in Mice: Contribution of 5-HT2A and 5-HT1A Receptors.

Neural synchrony and functional connectivity are disrupted in schizophrenia. We investigated changes in prefrontal-hippocampal neural dynamics during psychosis-like states induced by the NMDAR antagonist phencyclidine and subsequent rescue by two atypical antipsychotic drugs (AAPDs), risperidone and clozapine, and the classical APD haloperidol. The psychotomimetic effects of phencyclidine were associated with prefrontal hypersynchronization, hippocampal desynchronization, and disrupted circuit connectivity. Phencyclidine boosted prefrontal oscillatory power at atypical bands within delta, gamma, and high frequency ranges, while irregular cross-frequency and spike-LFP coupling emerged. In the hippocampus, phencyclidine enhanced delta rhythms but suppressed theta oscillations, theta-gamma coupling, and theta-beta spike-LFP coupling. Baseline interregional theta-gamma coupling, theta phase coherence, and hippocampus-to-cortex theta signals were redirected to delta frequencies. Risperidone and clozapine, but not haloperidol, reduced phencyclidine-induced prefrontal and cortical-hippocampal hypersynchrony. None of the substances restored hippocampal and circuit desynchronization. These results suggest that AAPDs, but not typical APDs, target prefrontal-hippocampal pathways to elicit antipsychotic action. We investigated whether the affinity of AAPDs for serotonin receptors could explain their distinct effects. Serotonin 5-HT2AR antagonism by M100907 and 5-HT1AR agonism by 8-OH-DPAT reduced prefrontal hypersynchronization. Our results point to fundamentally different neural mechanisms underlying the action of atypical versus typical APDs with selective contribution of serotonin receptors.

Prefrontal-hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability.

Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.

Postnatal environmental enrichment enhances memory through distinct neural mechanisms in healthy and trisomic female mice.

Stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to improve cognitive impairment due to intellectual disability, aging, and neurodegeneration, however the underlying neural mechanisms are poorly understood. We investigated the neural correlates of memory amelioration produced by postnatal environmental enrichment (EE) in diploid mice and the Ts65Dn mouse model of Down syndrome (trisomy 21). We recorded neural activities in brain structures key for memory processing, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in non-enriched or enriched environments. Enriched wild-type animals exhibited enhanced neural synchrony in the hippocampus across different brain states (increased gamma oscillations, theta-gamma coupling, sleep ripples). Trisomic females showed increased theta and gamma rhythms in the hippocampus and prefrontal cortex across different brain states along with enlarged ripples and disrupted circuit gamma signals that were associated with memory deficits. These pathological activities were attenuated in their trisomic EE-reared peers. Our results suggest distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE and put forward hippocampal-prefrontal hypersynchrony and miscommunication as major targets underlying the beneficial effects of EE in intellectual disability.

Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals.

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

Methylphenidate Attenuates the Cognitive and Mood Alterations Observed in Mbnl2 Knockout Mice and Reduces Microglia Overexpression.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.

Neural Substrates of Dopamine D2 Receptor Modulated Executive Functions in the Monkey Prefrontal Cortex.

Dopamine D2 receptors (D2R) play a major role in cognition, mood and motor movements. Their blockade by antipsychotic drugs reduces hallucinatory and delusional behaviors in schizophrenia, but often fails to alleviate affective and cognitive dysfunctions. The prefrontal cortex (PFC) expresses D2R and is altered in schizophrenia. We investigated how D2R modulate behavior and PFC function in monkeys. Two monkeys learned new and performed highly familiar visuomotor associations, where each cue was associated with a saccade to a right or left target. We recorded neural spikes and local field potentials from multiple electrodes while injecting the D2R antagonist eticlopride in the lateral PFC. Blocking prefrontal D2R impaired associative learning and cognitive flexibility, reduced motivation, but left the performance of familiar associations intact. Eticlopride reduced saccade-direction selectivity of prefrontal neurons, leading to a decrease in neural information about the associations, and an increase in alpha oscillations. These results, together with our recent study using a D1R antagonist, suggest that D1R and D2R in the primate lateral PFC cooperate to modulate several executive functions. Our findings help to gain insight into why antipsychotic drugs, with strong antagonistic actions on D2R, fail to ameliorate cognitive and emotional deficits in schizophrenia.

Nanoporous graphene-based thin-film microelectrodes for in vivo high-resolution neural recording and stimulation.

One of the critical factors determining the performance of neural interfaces is the electrode material used to establish electrical communication with the neural tissue, which needs to meet strict electrical, electrochemical, mechanical, biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin-film technology and its engineering to form flexible neural interfaces. The developed technology allows the fabrication of small microelectrodes (25 µm diameter) while achieving low impedance (∼25 kΩ) and high charge injection (3-5 mC cm-2). In vivo brain recording performance assessed in rodents reveals high-fidelity recordings (signal-to-noise ratio >10 dB for local field potentials), while stimulation performance assessed with an intrafascicular implant demonstrates low current thresholds (<100 µA) and high selectivity (>0.8) for activating subsets of axons within the rat sciatic nerve innervating tibialis anterior and plantar interosseous muscles. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical (12 week) and intraneural (8 week) implantation. This work describes a graphene-based thin-film microelectrode technology and demonstrates its potential for high-precision and high-resolution neural interfacing.

Neural substrates of cognitive impairment in a NMDAR hypofunction mouse model of schizophrenia and partial rescue by risperidone.

N-methyl D-aspartate receptor (NMDAR) hypofunction is a pathophysiological mechanism relevant for schizophrenia. Acute administration of the NMDAR antagonist phencyclidine (PCP) induces psychosis in patients and animals while subchronic PCP (sPCP) produces cognitive dysfunction for weeks. We investigated the neural correlates of memory and auditory impairments in mice treated with sPCP and the rescuing abilities of the atypical antipsychotic drug risperidone administered daily for two weeks. We recorded neural activities in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC) during memory acquisition, short-term, and long-term memory in the novel object recognition test and during auditory processing and mismatch negativity (MMN) and examined the effects of sPCP and sPCP followed by risperidone. We found that the information about the familiar object and its short-term storage were associated with mPFC→dHPC high gamma connectivity (phase slope index) whereas long-term memory retrieval depended on dHPC→mPFC theta connectivity. sPCP impaired short-term and long-term memories, which were associated with increased theta power in the mPFC, decreased gamma power and theta-gamma coupling in the dHPC, and disrupted mPFC-dHPC connectivity. Risperidone rescued the memory deficits and partly restored hippocampal desynchronization but did not ameliorate mPFC and circuit connectivity alterations. sPCP also impaired auditory processing and its neural correlates (evoked potentials and MMN) in the mPFC, which were also partly rescued by risperidone. Our study suggests that the mPFC and the dHPC disconnect during NMDAR hypofunction, possibly underlying cognitive impairment in schizophrenia, and that risperidone targets this circuit to ameliorate cognitive abilities in patients.

Serotonin modulates fast-spiking interneuron and synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors.

Alterations of the serotonergic system in the prefrontal cortex (PFC) are implicated in psychiatric disorders such as schizophrenia and depression. Although abnormal synchronous activity is observed in the PFC of these patients, little is known about the role of serotonin (5-HT) in cortical synchrony. We found that 5-HT, released by electrical stimulation of the dorsal raphe nucleus (DRN) in anesthetized rats, regulates the frequency and the amplitude of slow (<2 Hz) waves in the PFC via 5-HT(2A) receptors (5-HT(2A)Rs). 5-HT also modulates prefrontal gamma (30-80 Hz) rhythms through both 5-HT(1A)Rs and 5-HT(2A)Rs, but not 5-HT(2C)Rs, inducing an overall decrease in the amplitude of gamma oscillations. Because fast-spiking interneurons (FSi) are involved in the generation of gamma waves, we examined serotonergic modulation of FSi activity in vivo. Most FSi are inhibited by serotonin through 5-HT(1A)Rs, while a minority is activated by 5-HT(2A)Rs, and not 5-HT(2C)Rs. In situ hybridization histochemistry confirmed that distinct populations of FSi in the PFC express 5-HT(1A)Rs and 5-HT(2A)Rs, and that the number of FSi expressing 5-HT(2C)Rs is negligible. We conclude that 5-HT exerts a potent control on slow and gamma oscillations in the PFC. On the one hand, it shapes the frequency and amplitude of slow waves through 5-HT(2A)Rs. On the other hand, it finely tunes the amplitude of gamma oscillations through 5-HT(2A)R- and 5-HT(1A)R-expressing FSi, although it primarily downregulates gamma waves via the latter population. These results may provide insight into impaired serotonergic control of network activity in psychiatric illnesses such as schizophrenia and depression.

Serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors strongly influence prefronto-hippocampal neural networks in alert mice: Contribution to the actions of risperidone.

Atypical antipsychotic drugs (APDs) used to treat positive and negative symptoms in schizophrenia block serotonin receptors 5-HT2AR and dopamine receptors D2R and stimulate 5-HT1AR directly or indirectly. However, the exact cellular mechanisms mediating their therapeutic actions remain unresolved. We recorded neural activity in the prefrontal cortex (PFC) and hippocampus (HPC) of freely-moving mice before and after acute administration of 5-HT1AR, 5-HT2AR and D2R selective agonists and antagonists and atypical APD risperidone. We then investigated the contribution of the three receptors to the actions of risperidone on brain activity via statistical modeling and pharmacological reversal (risperidone + 5-HT1AR antagonist WAY-100635, risperidone + 5-HT2A/2CR agonist DOI, risperidone + D2R agonist quinpirole). Risperidone, 5-HT1AR agonism with 8-OH-DPAT, 5-HT2AR antagonism with M100907, and D2R antagonism with haloperidol reduced locomotor activity of mice that correlated with a suppression of neural spiking, power of theta and gamma oscillations in PFC and HPC, and reduction of PFC-HPC theta phase synchronization. By contrast, activation of 5-HT2AR with DOI enhanced high-gamma oscillations in PFC and PFC-HPC high gamma functional connectivity, likely related to its hallucinogenic effects. Together, power changes, regression modeling and pharmacological reversals suggest an important role of 5-HT1AR agonism and 5-HT2AR antagonism in risperidone-induced alterations of delta, beta and gamma oscillations, while D2R antagonism may contribute to risperidone-mediated changes in delta oscillations. This study provides novel insight into the neural mechanisms for widely prescribed psychiatric medication targeting the serotonin and dopamine systems in two regions involved in the pathophysiology of schizophrenia.

Serotonin Modulation of Prefronto-Hippocampal Rhythms in Health and Disease.

There is mounting evidence that most cognitive functions depend upon the coordinated activity of neuronal networks often located far from each other in the brain. Ensembles of neurons synchronize their activity, generating oscillations at different frequencies that may encode behavior by allowing an efficient communication between brain areas. The serotonin system, by virtue of the widespread arborisation of serotonergic neurons, is in an excellent position to exert strong modulatory actions on brain rhythms. These include specific oscillatory activities in the prefrontal cortex and the hippocampus, two brain areas essential for many higher-order cognitive functions. Psychiatric patients show abnormal oscillatory activities in these areas, notably patients with schizophrenia who display psychotic symptoms as well as affective and cognitive impairments. Synchronization of neural activity between the prefrontal cortex and the hippocampus seems to be important for cognition and, in fact, reduced prefronto-hippocampal synchrony has been observed in a genetic mouse model of schizophrenia. Here, we review recent advances in the field of neuromodulation of brain rhythms by serotonin, focusing on the actions of serotonin in the prefrontal cortex and the hippocampus. Considering that the serotonergic system plays a crucial role in cognition and mood and is a target of many psychiatric treatments, it is surprising that this field of research is still in its infancy. In that regard, we point to future investigations that are much needed in this field.

Dopamine modulation of learning and memory in the prefrontal cortex: insights from studies in primates, rodents, and birds.

In this review, we provide a brief overview over the current knowledge about the role of dopamine transmission in the prefrontal cortex during learning and memory. We discuss work in humans, monkeys, rats, and birds in order to provide a basis for comparison across species that might help identify crucial features and constraints of the dopaminergic system in executive function. Computational models of dopamine function are introduced to provide a framework for such a comparison. We also provide a brief evolutionary perspective showing that the dopaminergic system is highly preserved across mammals. Even birds, following a largely independent evolution of higher cognitive abilities, have evolved a comparable dopaminergic system. Finally, we discuss the unique advantages and challenges of using different animal models for advancing our understanding of dopamine function in the healthy and diseased brain.

Serotonin modulation of cortical neurons and networks.

The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe.

The role of prefrontal dopamine D1 receptors in the neural mechanisms of associative learning.

Dopamine is thought to play a major role in learning. However, while dopamine D1 receptors (D1Rs) in the prefrontal cortex (PFC) have been shown to modulate working memory-related neural activity, their role in the cellular basis of learning is unknown. We recorded activity from multiple electrodes while injecting the D1R antagonist SCH23390 in the lateral PFC as monkeys learned visuomotor associations. Blocking D1Rs impaired learning of novel associations and decreased cognitive flexibility but spared performance of already familiar associations. This suggests a greater role for prefrontal D1Rs in learning new, rather than performing familiar, associations. There was a corresponding greater decrease in neural selectivity and increase in alpha and beta oscillations in local field potentials for novel than for familiar associations. Our results suggest that weak stimulation of D1Rs observed in aging and psychiatric disorders may impair learning and PFC function by reducing neural selectivity and exacerbating neural oscillations associated with inattention and cognitive deficits.

Serotonin and prefrontal cortex function: neurons, networks, and circuits.

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.

The hallucinogen DOI reduces low-frequency oscillations in rat prefrontal cortex: reversal by antipsychotic drugs.

BACKGROUND: Perceptual and psychic alterations and thought disorder are fundamental elements of schizophrenia symptoms, a pathology associated with an abnormal macro- and microcircuitry of several brain areas including the prefrontal cortex (PFC). Alterations in information processing in PFC may partly underlie schizophrenia symptoms. METHODS: The 5-HT(2A/2C) agonist DOI and antipsychotic drugs were administered to anesthetized rats. Single unit and local field potential (LFP) extracellular recordings were made in medial PFC (mPFC). Electrolytic lesions were performed in the thalamic nuclei. RESULTS: DOI markedly disrupts cellular and network activity in rat PFC. DOI altered pyramidal discharge in mPFC (39% excited, 27% inhibited, 34% unaffected; n = 51). In all instances, DOI concurrently reduced low-frequency oscillations (.3-4 Hz; power spectrum: .25 +/- .02 and .14 +/- .01 microV(2) in basal conditions and after 50-300 microg/kg intravenous (i.v.) DOI, respectively; n = 51). Moreover, DOI disrupted the temporal association between the active phase of LFP and pyramidal discharge. Both effects were reversed by M100907 (5-HT(2A) receptor antagonist) and were not attenuated by thalamic lesions, supporting an intracortical origin of the effects of DOI. The reduction in low-frequency oscillations induced by DOI was significantly reversed by the antipsychotic drugs haloperidol (.1-.2 mg/kg i.v.) and clozapine (1 mg/kg i.v.). CONCLUSIONS: DOI disorganizes network activity in PFC, reducing low-frequency oscillations and desynchronizing pyramidal discharge from active phases of LFP. These effects may underlie DOI's psychotomimetic action. The reversal by clozapine and haloperidol indicates that antipsychotic drugs may reduce psychotic symptoms by normalizing an altered PFC function.

Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: involvement of serotonin and GABA.

Serotonin is involved in psychiatric disorders exhibiting abnormal prefrontal cortex (PFC) function (e.g. major depression, schizophrenia). We examined the effect of the stimulation of the dorsal and median raphe nuclei (DR and MnR, respectively) on the activity of PFC neurons. Electrical stimulation of DR/MnR inhibited 66% (115/173) of pyramidal neurons in the medial PFC (mPFC). The rest of the cases exhibited orthodromic excitations, either pure (13%) or preceded by short-latency inhibitions (20%). Excited neurons had a lower pre-stimulus firing rate than those inhibited. Excitations evoked by MnR stimulation had a shorter latency than those evoked by DR stimulation. WAY-100635 [a 5-hydroxytryptamine1A (5-HT1A) antagonist] and the selective gamma aminobutyric acidA (GABAA) antagonist picrotoxinin partially antagonized DR/MnR-evoked inhibitions, suggesting the involvement of 5-HT1A- and GABAA-mediated components. The presence of a direct DR/MnR-mPFC GABAergic component is suggested by the short latency of evoked inhibitions (9 +/- 1 ms), faster than those evoked in the secondary motor area (20 +/- 3 ms), and that of antidromic spikes evoked by DR/MnR stimulation in mPFC pyramidal neurons (15 +/- 1 ms). Stimulation of the DR/MnR with paired pulses enhanced the duration of inhibitions and turned some excitations into inhibitions. Thus, the DR/MnR control the activity of mPFC pyramidal neurons in vivo in a complex manner, involving 5-HT-mediated excitations and GABA- and 5-HT-mediated inhibitions.

Control of the serotonergic system by the medial prefrontal cortex: potential role in the etiology of PTSD and depressive disorders.

The prefrontal cortex is involved in an array of higher brain functions that are altered in psychiatric disorders. Serotonergic neurons of the midbrain rapbe nuclei innervate the prefrontal cortex and are the cellular target for drugs used to treat mood disorders such as the selective serotonin (5-HT) reuptake inhibitors. Anatomical evidence supports the existence of projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DR). We report on a functional control of the activity of DR 5-HT neurons by projection neurons in the mPFC. The stimulation of the mPFC elicits two types of responses in DR 5-HT neurons, orthodromic excitations and inhibitions. Excitations are mediated by AMPA/KA and NMDA receptors whereas inhibitions are mediated by GABA(A) and 5-HT(1A) receptors. The activation of a subgroup of 5-HT neurons increases 5-HT release which subsequently activates 5-HT(1A) autoreceptors on other 5-HT neurons. GABA(A)-mediated inhibitions involve GABAergic elements in the DR or adjacent areas. Pyramidal neurons of the mPFC co-express postsynaptic 5-HT(1A) (inhibitory) and 5-HT(2A) (excitatory) receptors. Consistent with the above observations, the selective activation of both receptors in mPFC reduced and increased, respectively, the firing activity of DR 5-HT neurons and the 5-HT release in mPFC. Overall, these data indicate that the activity of the 5-HT system is strongly controlled by the mPFC. Thus, the abnormal prefrontal function in post-traumatic stress disorder and depressive patients may induce a disregulation of 5-HT neurons projecting to other brain areas that can underlie the existing symptomatology in these psychiatric disorders.