Bernat Kocsis

Prominent Burst Firing of Dopaminergic Neurons in the Ventral Tegmental Area during Paradoxical Sleep

Dopamine is involved in motivation, memory, and reward processing. However, it is not clear whether the activity of dopamine neurons is related or not to vigilance states. Using unit recordings in unanesthetized head restrained rats we measured the firing pattern of dopamine neurons of the ventral tegmental area across the sleep–wake cycle. We found these cells were activated during paradoxical sleep (PS) via a clear switch to a prominent bursting pattern, which is known to induce large synaptic dopamine release. This activation during PS was similar to the activity measured during the consumption of palatable food. Thus, as it does during waking in response to novelty and reward, dopamine could modulate brain plasticity and thus participate in memory consolidation during PS. By challenging the traditional view that dopamine is the only aminergic group not involved in sleep physiology, this study provides an alternative perspective that may be crucial for understanding the physiological function of PS and dream mentation.

Activation of Cannabinoid-1 Receptors Disrupts Sensory Gating and Neuronal Oscillation: Relevance to Schizophrenia

BACKGROUND Impaired auditory gating and abnormal neuronal synchrony are indicators of dysfunctional information processing in schizophrenia patients and possible underlying mechanisms of their impaired sensory and cognitive functions. Because cannabinoid receptors and endocannabinoids have been linked to psychiatric disorders, including schizophrenia, the aim of this study was to evaluate the effects of cannabinoid-1 (CB1) receptor activation on sensory gating and neuronal oscillations in rats. METHODS Auditory sensory gating has been recorded from the hippocampus and entorhinal cortex (EC) in anesthetized rats. Neuronal network oscillations were recorded from the hippocampus, medial septum, EC, and medial prefrontal cortex in anesthetized and freely moving rats. Effects of systemic administration of CB1 receptor agonist CP-55940 were evaluated on these parameters. RESULTS CP-55940 significantly disrupted auditory gating both in the hippocampus and EC in anesthetized rats. Theta field potential oscillations were disrupted in the hippocampus and EC, with simultaneous interruption of theta-band oscillations of septal neurons. Administration of the CB1 receptor antagonist AM-251 reversed both the agonist-induced gating deficit and the diminished oscillations. In freely moving rats, CP-55940 significantly reduced theta and gamma power in the hippocampus, whereas in the EC, only gamma power was attenuated. However, novelty-induced theta and gamma activities were significantly diminished by CP-55940 in both the hippocampus and EC. CONCLUSIONS Our data indicate that activation of CB1 receptors interferes with neuronal network oscillations and impairs sensory gating function in the limbic circuitry, further supporting the connection between cannabis abuse and increased susceptibility of developing schizophrenia spectrum disorders.

Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function?

Hippocampal damage produces cognitive deficits similar to dementia and changes in emotional and motivated reactions similar to anxiolytic drugs. The gross electrical activity of the hippocampus contains a marked ‘theta rhythm’. This is a relatively high voltage sinusoidal waveform, resulting from synchronous phasic firing of cells, variation in which correlates with behavioural state. Like the hippocampus, theta has been linked to both cognitive and emotional functions. Critically, it has recently been shown that restoration of theta-like rhythmicity can restore lost cognitive function. We review the effects of systemic administration of drugs on hippocampal theta elicited by stimulation of the reticular formation. We conclude that reductions in the frequency of reticular-elicited theta provide what is currently the best in-vivo means of detecting antianxiety drugs. We also suggest that increases in the power of reticular-elicited theta could detect drugs useful in the treatment of disorders, such as dementia, that involve memory loss. We argue that these functionally distinct effects should be seen as indirect and that each results from a change in a single form of cognitive–emotional processing that particularly involves the hippocampus.

Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus

Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico‐limbic‐striatal circuits input into the 5‐HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5‐HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5‐HT and non‐5‐HT, putative γ‐amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5‐HT neurons (regular, slow firing, broad spike width) and 21 non‐5‐HT, putative GABA neurons (fast‐firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5‐HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12–20 ms) poststimulus facilitation of 10/21 non‐5‐HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5‐HT neurons and non‐5‐HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5‐HT neurons.

Differential Role of NR2A and NR2B Subunits in N-Methyl-D-Aspartate Receptor Antagonist-Induced Aberrant Cortical Gamma Oscillations

BACKGROUND N-methyl-D-aspartate receptor (NMDA-R) hypofunction plays an important role in cognitive impairment in schizophrenia. NMDA-R antagonists elicit psychotic symptoms in humans and schizophrenia-relevant signs in rodents, including a strong increase in cortical gamma activity. NMDA-Rs are composed of different subunits, and accumulating evidence indicates that neuronal damage due to NMDA-R antagonists depends on their action on a specific type of the receptor containing the NR2A subunit. In human schizophrenics, NR2A is selectively reduced in fast-firing interneurons. These neurons are critical for gamma oscillations, indicating that pathological changes in gamma activity may depend on subunit-specific NMDA-R deficit. The present study tested this hypothesis. METHODS Cortical electroencephalograms were recorded in freely moving rats and the changes in gamma power were measured after administration of NMDA-R antagonists with different subunit selectivity, including NR2A-preferring (PEAQX, n = 5; NVP-AAM077, n = 18), NR2B-selective (ifenprodil, n = 6; threo-ifenprodil, n = 4; Ro25-6985, n = 13), and NR2C/D-selective (n = 8) antagonists, along with vehicle and nonselective NMDA-R antagonists (ketamine, n = 10; MK801, n = 12). Changes in prepulse inhibition of startle was tested after MK-801 (n = 6), NVP-AAM077, and Ro-6891 (n = 5) injection. RESULTS Strong increase in gamma power was induced by nonselective NMDA-R antagonists and by blockade of NMDA-Rs containing the NR2A subunit, with co-occurring gating deficits and diminished low-frequency modulation of gamma oscillations. In contrast, selective blockade of NR2B, C, or D subunit-containing receptors had minor effects. CONCLUSIONS Major subtype-specific differences in the role of NMDA-Rs in cortical gamma oscillation may have implications for the pathomechanism and treatment of cognitive impairment in schizophrenia.

Pharmacological suppression of the median raphe nucleus with serotonin1a agonists, 8-OH-DPAT and buspirone, produces hippocampal theta rhythm in the rat

The effects on the hippocampal electroencephalogram of microinjections of procaine hydrochloride and the serotonin1A agonists, 8-OH-DPAT and buspirone, into the median raphe nucleus were examined in the urethane anesthetized rat. Injections of procaine, 8-OH-DPAT or buspirone into the median raphe nucleus produced a change in the hippocampal electroencephalogram from a spontaneous desynchronized pattern to a synchronized pattern (theta rhythm) within short latencies and for long durations post-injection. Procaine was shown to elicit theta at a mean latency of 52 s and for a mean duration of 21.75 min; buspirone at a mean latency of 2 min and for a mean duration of 34.5 min. A dose dependent relationship was observed between 8-OH-DPAT injections and latencies but not durations. Small doses (0.5 micrograms) of 8-OH-DPAT produced theta at a mean latency of 1.33 min and large doses (3.0 micrograms) at a mean latency of 1.17 min. 8-OH-DPAT injections generated theta for a mean duration of 62 min. Injections of each of these substances into structures dorsal, lateral or rostrocaudal to the median raphe (dorsal raphe nucleus, pontine reticular formation, caudal linear nucleus or raphe pontis, respectively) failed to generate theta or in a few cases produced theta at very long latencies (> 24 min). Saline injections in the median raphe nucleus or control structures were without effect. The demonstration that agents injected into the median raphe nucleus that inhibit its activity (procaine and serotonin1A agonists) produce theta indicate that serotonin-containing median raphe neurons normally suppress theta or are involved in the control of hippocampal desynchronization. The present findings are consistent with previous work showing that median raphe nucleus stimulation desynchronizes the hippocampal electroencephalogram and that median raphe nucleus lesions produce constant theta, but are at odds with the proposal that serotonergic mechanisms may play a role in the generation of the theta rhythm.

Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations

Significance When we are awake, purposeful thinking and behavior require the synchronization of brain cells involved in different aspects of the same task. Cerebral cortex electrical oscillations in the gamma (30–80 Hz) range are particularly important in such synchronization. In this report we identify a particular subcortical cell type which has increased activity during waking and is involved in activating the cerebral cortex and generating gamma oscillations, enabling active cortical processing. Abnormalities of the brain mechanisms controlling gamma oscillations are involved in the disordered thinking typical of neuropsychiatric disorders such as schizophrenia. Thus, these findings may pave the way for targeted therapies to treat schizophrenia and other disorders involving abnormal cortical gamma oscillations. Cortical gamma band oscillations (GBO, 30–80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia.

Theta synchronization in the limbic system: the role of Gudden's tegmental nuclei

Theta rhythm is most prominent in the hippocampus but has also been recorded in other cortical and limbic structures and can play an important role in functional coupling of widely separated structures responsible for different components of the memory building process. Here we demonstrate in the rat that neuronal activity exhibiting strong state‐dependent synchrony with rhythmic hippocampal electroencephalogram is present also at the brainstem level, specifically in the relatively small tegmental nuclei of Gudden intimately connected with the limbic forebrain. We found that during theta states, either occurring spontaneously or triggered by sensory stimulation in the urethane anaesthetized rat, all neurons in the anterior and ventral tegmental nuclei exhibited a consistent switch from irregular discharges to rhythmic bursts. The switch between these patterns closely matched the analogous transformations in the hippocampal EEG, but the level of synchrony between the two signals varied depending on the level of theta activation. During sensory stimulation, when theta is faster and more regular, the rhythmic bursts in the tegmentum showed extremely high coherence (up to 0.96) with hippocampal field potentials. During spontaneous theta, the average coherence was lower but still highly significant (0.62). Guddens nuclei are reciprocally connected to the mammillary body complex (MB) occupying a strategic position at the gateway of hippocampofugal connections organized in the Papez circuit. Thus, coupling between the MB‐Gudden circuit and the hippocampus and consequently the neuronal traffic through the Papez circuit and hence the assembly of limbic structures connected to the hippocampus may vary according to the activity in these specific brainstem nuclei.

The supramammillary nucleus: Is it necessary for the mediation of hippocampal theta rhythm?

Recent evidence suggests that the supramammillary nucleus of the posterior hypothalamus serves as an important relay in a brainstem to septum/hippocampus pathway involved in the generation of hippocampal theta rhythm. In order to examine the role of the supramammillary nucleus as a possible relay/mediator of hippocampal theta rhythm, electrolytic lesions and procaine injections were administered to the supramammillary nucleus of freely moving and urethane-anesthetized rats, respectively. In the urethane-anesthetized rat, it was found that procaine injections attenuated both the frequency and amplitude of theta rhythm elicited by stimulation of the pontine reticular formation. These data suggest that the pontine reticular elicitation of hippocampal theta rhythm is mediated through connections with the supramammillary nucleus. However, it was found that lesions of the supramammillary nucleus failed to produce significant changes in the hippocampal electroencephalogram of freely moving animals. Several explanations concerning this apparent discrepancy are discussed. The most compelling is that multiple brainstem to septum/hippocampus pathways may serve to generate or facilitate the generation of theta rhythm in the freely moving animal. The present report demonstrates that the supramammillary nucleus plays a questionable role in the mediation of hippocampal electroencephalogram signals which are thought to be important for mnemonic processes.

Possible glutamatergic/aspartatergic projections to the supramammillary nucleus and their origins in the rat studied by selective [3H]D-aspartate labelling and immunocytochemistry

The supramammillary neurons projecting directly to the hippocampus or indirectly via the septum participate in the regulation of hippocampal theta activity. Inputs to the supramammillary nucleus are only partly specified neurochemically. Glutamate appears to be an excitatory transmitter in this cell group, however, the origin of the glutamatergic afferents is unknown. The present investigations were devoted to study this question. The transmitter-selective [(3)H]D-aspartate retrograde transport method was used injecting the tracer into the lateral subregion of the nucleus. The radioactive tracer was visualized by autoradiography. Non-selective retrograde tracing experiments were also performed for reference injecting wheat germ agglutinin-conjugated colloidal gold into the same supramammillary region. Retrogradely radiolabelled neurons in various numbers were detected in several brain regions including medial septum-diagonal band complex, lateral septum, rostral part of medial and lateral preoptic areas, lateral habenula, ventral premammillary nucleus, apical subregion of interpeduncular nucleus, laterodorsal tegmental nucleus, and dorsal and median raphe nuclei. Radiolabelled neurons in the mentioned raphe nuclei were serotonin-immunonegative. In the non-selective retrograde tracing experiments combined with immunocytochemistry, about 50% of the retrogradely labelled neurons in the raphe nuclei was serotonin-immunonegative, showing that not only serotonergic raphe neurons project to the supramammillary nucleus. The findings indicate that a significant part of the afferents from telencephalic, diencephalic and brainstem regions to the supramammillary nucleus may contain glutamate/aspartate as neurotransmitter. The most important functional implications of these observations concern the role of the supramammillary nucleus in controlling the electrical activity of the hippocampus, and in particular the generation and maintenance of the theta rhythm.