Effects of pre-training injection of orexin A into dorsal raphe nucleus in passive avoidance acquisition on male rats

AbstractEndogenous orexins, especially orexin A, play an important role in spatial learning and memory. A recent study has shown the effect of orexinergic system in hippocampus on avoidance learning. Orexinergic receptors are distributed in dorsal raphe nucleus (DRN). The aim of this study was to evaluate the role of dorsal raphe orexinergic system in passive avoidance learning (PA). Rats were implanted with the cannula aimed at dorsal raphe nucleus. Orexin A or saline were injected into the DRN prior to avoidance training. Pre-training orexin type 1 receptors activation in DRN impaired passive avoidance acquisition but had no effect on PA retention

Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleu

We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are ten kinds of voltage dependent ion channels as well as calcium-dependent potassium current. Calcium dynamics includes buffering and pumping. In sections 3-9, each component is considered in detail and parameters estimated from voltage clamp data where possible. In the next two sections simplified versions of some components are employed to explore the effects of various parameters on spiking, using a systematic approach, ending up with the following eleven components: a fast sodium current $I_{Na}$, a delayed rectifier potassium current $I_{KDR}$, a transient potassium current $I_A$, a low-threshold calcium current $I_T$, two high threshold calcium currents $I_L$ and $I_N$, small and large conductance potassium currents $I_{SK}$ and $I_{BK}$, a hyperpolarization-activated cation current $I_H$, a leak current $I_{Leak}$ and intracellular calcium ion concentration $Ca_i$. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, pacemaker-like spiking and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have kinks or notches as have been reported in some experimental studies. The computed time courses of $I_A$ and $I_T$ during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous spiking could be obtained with small changes in a few parameters from their values with driven spiking.Comment: The abstract has been truncate

Melanin-Concentrating Hormone (MCH): Role in REM Sleep and Depression.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD

Modelling the Effect of Dorsal Raphe Serotonin Neurons on Patience for Future Rewards

Serotonin is a neurotransmitter that is implicated in many basic human functions and behaviours and is closely associated with happiness, depression and reward processing. In particular it appears to be involved in suppressing responses to distracting stimuli while waiting for a delayed reward. Here we present a system level model of the limbic system which is able to generate a serotonin (5-hydroxytryptamine [5HT]) signal so that a simulated animal waits for a delayed reward. We propose that the 5HT signal is computed by a network involving the medial Orbital Frontal Cortex (mOFC), medial Pre Frontal Cortex (mPFC), Dorsal Raphe Nucleus (DRN)and the Nucleus Accumbens Core (NAcc). The serotonin signal encodes pre-reward liking, motivation throughout the trial and delayed reward waiting. We have successfully replicated the behaviour and dynamics of laboratory studies. With the help of this model we can predict that low levels of serotonin indirectly cause less encountered rewards because the animal gives up too early

Functional Connectivity of the Raphe Nuclei: Link to Tobacco Withdrawal in Smokers.

BackgroundAlthough nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies.MethodsFunctional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers.ResultsConnectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal.ConclusionsRelief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking

Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine

Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.Funding: This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13-00038 and PI16-00217) that were cofunded by the European Regional Development Fund (“A way to build Europe”). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)

ULTRASONIC VOCALIZATIONS AND STRESS RESILIENCE: BEHAVIORAL AND NEUROBIOLOGICAL CORRELATES

When we are exposed to a traumatic or stressful life event, some individuals may develop symptoms of anxiety or depression while others may appear unaffected. In humans and nonhuman organisms, the ability to cope plays a large role in how an organism responds to a stressor, and this coping may be influenced by innate mechanisms. We have identified the use of ultrasonic vocalizations during intermittent swim stress (ISS) to forecast innate behavioral differences in stress reactivity. Vocalizing rats are resilient as they exhibit less cognitive impairment, motivational changes, and fewer anxiety-like behaviors typically observed post-ISS. Resilience should be associated with an active, stress buffering coping strategy during ISS, whereas non-vocalizing should exhibit more passive behaviors. These active or passive behaviors are driven by a corticolimbic serotonergic circuit originating in the dorsal raphe nucleus. Active coping is associated with reduced dorsal raphe serotonin activity, which leads to reduced post-stress impairment. We hypothesized vocalizing rats would engage in active coping responses, display fewer anxiety-like behaviors, and exhibit decreased serotonergic activation in the dorsal raphe nucleus compared with non-vocalizing rats. We found vocalizing rats exhibited reduced post-stress social anxiety, but engaged in passive coping during stress. Vocalizing rats further exhibited increased serotonergic activity in stress-responsive subregions of the dorsal raphe nucleus compared to non-vocalizing and unstressed controls. These data are the first to verify the coping strategy and associated serotonergic activity of vocalizing rats as a novel model of stress resilience