Pavel E. Rueda-Orozco

Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

Diversity in long-term synaptic plasticity at inhibitory synapses of striatal spiny neurons

Procedural memories and habits are posited to be stored in the basal ganglia, whose intrinsic circuitries possess important inhibitory connections arising from striatal spiny neurons. However, no information about long-term plasticity at these synapses is available. Therefore, this work describes a novel postsynaptically dependent long-term potentiation (LTP) at synapses among spiny neurons (intrinsic striatal circuitry); a postsynaptically dependent long-term depression (LTD) at synapses between spiny and pallidal neurons (indirect pathway); and a presynaptically dependent LTP at strionigral synapses (direct pathway). Interestingly, long-term synaptic plasticity differs at these synapses. The functional consequences of these long-term plasticity variations during learning of procedural memories are discussed.

BCL-2 and BAX proteins expression throughout the light–dark cycle and modifications induced by sleep deprivation and rebound in adult rat brain

It has been suggested that sleep has a restorative function; however, experimental support is limited. Hence, we investigated whether changes in the level of antiapoptotic BCL‐2 protein and proapoptotic BAX protein occur during sleep deprivation (SD) and sleep rebound, and evaluated the spontaneous changes in these proteins, along the light–dark cycle, in the adult male Wistar rat. Estimations were made in the prefrontal cortex, hippocampus, striatum, and pons. We observed that BCL‐2 exhibited diurnal variations in the prefrontal cortex and striatum, whereas BAX varied in the striatum and showed only small variations in the pons as measured by immunoblotting. The BCL‐2/BAX ratio exhibited diurnal variations in the prefrontal cortex and striatum. BCL‐2 and BAX levels were affected by 24 hr of total SD and 24 hr of sleep rebound. SD decreased the BCL‐2/BAX ratio in the prefrontal cortex and pons. Sleep rebound increased the BCL‐2/BAX ratio in the hippocampus. In conclusion, the BCL‐2/BAX ratio is high during the dark phase as compared with the light phase in the prefrontal cortex and during the light phase as compared with the dark phase in the striatum. SD decreased the BCL‐2/BAX ratio in the prefrontal cortex and pons, whereas sleep rebound increased it in the hippocampus. These changes point out structures in the brain that express these proteins as a response to the light–dark cycle. Similarly, SD and sleep rebound seem to change these proteins expression in some other brain structures, suggesting that cellular vulnerability might be altered by these changes.

Nicotine prevents HIVgp120-caused electrophysiological and motor disturbances in rats

Human immunodeficiency virus (HIV)-associated dementia (HAD) is a frequent complication in HIV+ subjects. Several electrophysiological markers and motor control are altered in HIV+ subjects, including event-related potentials (N2-P3 changes). These are electrophysiological indicators of cognitive processing. The mechanisms by which HIV induces neurophysiological abnormality is still under research. However, several neurotransmitters have been implicated. For example, glutamate and the vasoactive intestinal neuropeptide (VIP). In this study, we support further this notion indicating that HIVgp120, a glycoprotein derived from HIV, is involved in the pathogenesis of neuropsychiatric abnormalities. We also have observations suggesting that one HIVgp120 mechanism of action is to interfere with cholinergic neurotransmission. Our results indicate that event-related potentials (ERP) were affected by HIVgp120, in particular N2 and P3. In addition, motor coordination was severely affected. Both parameters were maintained near normality when rats were simultaneously treated with nicotine. These results support further an HIVgp120-caused alteration of cholinergic neurotransmission that might be part of the etiology of neuropsychiatric disturbances.

Bidirectional plasticity in striatonigral synapses: A switch to balance direct and indirect basal ganglia pathways

There is no hypothesis to explain how direct and indirect basal ganglia (BG) pathways interact to reach a balance during the learning of motor procedures. Both pathways converge in the substantia nigra pars reticulata (SNr) carrying the result of striatal processing. Unfortunately, the mechanisms that regulate synaptic plasticity in striatonigral (direct pathway) synapses are not known. Here, we used electrophysiological techniques to describe dopamine D(1)-receptor-mediated facilitation in striatonigral synapses in the context of its interaction with glutamatergic inputs, probably coming from the subthalamic nucleus (STN) (indirect pathway) and describe a striatonigral cannabinoid-dependent long-term synaptic depression (LTD). It is shown that striatonigral afferents exhibit D(1)-receptor-mediated facilitation of synaptic transmission when NMDA receptors are inactive, a phenomenon that changes to cannabinoid-dependent LTD when NMDA receptors are active. This interaction makes SNr neurons become coincidence-detector switching ports: When inactive, NMDA receptors lead to a dopamine-dependent enhancement of direct pathway output, theoretically facilitating movement. When active, NMDA receptors result in LTD of the same synapses, thus decreasing movement. We propose that SNr neurons, working as logical gates, tune the motor system to establish a balance between both BG pathways, enabling the system to choose appropriate synergies for movement learning and postural support.

Global actions of nicotine on the striatal microcircuit.

The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

Muscarinic presynaptic modulation in GABAergic pallidal synapses of the rat.

The external globus pallidus (GPe) is central for basal ganglia processing. It expresses muscarinic cholinergic receptors and receives cholinergic afferents from the pedunculopontine nuclei (PPN) and other regions. The role of these receptors and afferents is unknown. Muscarinic M1-type receptors are expressed by synapses from striatal projection neurons (SPNs). Because axons from SPNs project to the GPe, one hypothesis is that striatopallidal GABAergic terminals may be modulated by M1 receptors. Alternatively, some M1 receptors may be postsynaptic in some pallidal neurons. Evidence of muscarinic modulation in any of these elements would suggest that cholinergic afferents from the PPN, or other sources, could modulate the function of the GPe. In this study, we show this evidence using striatopallidal slice preparations: after field stimulation in the striatum, the cholinergic muscarinic receptor agonist muscarine significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) from synapses that exhibited short-term synaptic facilitation. This inhibition was associated with significant increases in paired-pulse facilitation, and quantal content was proportional to IPSC amplitude. These actions were blocked by atropine, pirenzepine, and mamba toxin-7, suggesting that receptors involved were M1. In addition, we found that some pallidal neurons have functional postsynaptic M1 receptors. Moreover, some evoked IPSCs exhibited short-term depression and a different kind of modulation: they were indirectly modulated by muscarine via the activation of presynaptic cannabinoid CB1 receptors. Thus pallidal synapses presenting distinct forms of short-term plasticity were modulated differently.

A minority-ruled population coding of kinematics in the striatum

The structure of population activity in the dorsolateral striatum during the performance of motor sequences has not been characterized and it is unclear if striatal ensembles encode (predict) kinematic parameters defining how sequences are executed. Here we analyzed hundreds of striatal spike trains from naive and trained rats performing a running sequence. We found that the population response was composed of a diversity of phasic modulations covering the entire sequence. The accuracy of kinematics encoding by single neurons was around chance level but improved when neuronal ensembles were considered. The distribution of single-neuron contributions to ensemble encoding was highly skewed with a minority of neurons responsible for most of the encoding accuracy. Importantly, running speed ensemble encoding improved after learning. We propose that during motor learning, striatal ensembles adjust their task representation by tuning the activity of a minority of neurons to the kinematic parameters most relevant to motor performance.

Response outcomes gate the impact of expectations on perceptual decisions

Perceptual decisions are not only determined by current sensory information but are also influenced by expectations based on recent experiences. Can the impact of these expectations be flexibly modulated based on the outcome of previous decisions? We trained rats in several two-alternative forced choice auditory tasks, where the probability to repeat the previous stimulus category was varied in blocks of trials. All rats capitalized on the serial correlations of the stimulus sequence by consistently exploiting a transition bias: a tendency to repeat or alternate their previous response using an internal trial-by-trial estimate of the sequence repeating probability. Surprisingly, this bias was null in trials immediately following an error. The internal estimate however was not reset and it became effective again causing a bias after the next correct response. This ability to rapidly activate and inactivate the bias was captured by a non-linear generative model of rat behavior, whereby a reward-driven modulatory signal gated the use of the latent estimate of the environment statistics on the current decision. These results demonstrate that, based on the outcome of previous choices, rats flexibly modulate how expectations influence their current decisions.

Chloramphenicol decreases CB1 receptor expression in the nucleus accumbens and prefrontal cortex and prevents amphetamine-induced conditioned place preference in rats

Abstract Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug‐induced reward is a crucial effect for the development of drug‐dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)‐seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph‐induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30 min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home‐cage. Rats in group 2 were also treated with amph but received CAP (150 mg/kg sc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non‐experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph + veh group. These results support the notion that among the underlying mechanisms for amph‐seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning. HighlightsAmphetamine induces conditioned place preference and increases CB1 receptor expression in the NAcc.Chloramphenicol prevents amphetamine conditioned place preference and CB1 receptor increase expression in the NAcc.Chloramphenicol reduce CB1 receptor expression in the PFC.