Mapping learning and decision-making algorithms onto brain circuitry
In the first half of my talk, I will discuss our recent work on the midbrain dopamine system. The hypothesis that midbrain dopamine neurons broadcast an error signal for the prediction of reward is among the great successes of computational neuroscience. However, our recent results contradict a core aspect of this theory: that the neurons uniformly convey a scalar, global signal. I will review this work, as well as our new efforts to update models of the neural basis of reinforcement learning with our data. In the second half of my talk, I will discuss our recent findings of state-dependent decision-making mechanisms in the striatum.
PPN inputs to striatum
Mechanisms and Roles of Fast Dopamine Signaling
Dopamine is a neuromodulator that codes information on various time scales. I will discuss recent progress on the identification of fast release mechanisms for dopamine in the mouse striatum. I will present data on triggering mechanisms of dopamine release and evaluate its roles in striatal regulation. In the long-term, our work will allow for a better understanding of the mechanisms and time scales of dopamine coding in health and disease.
Experience-dependent remapping of temporal encoding by striatal ensembles
Medium-spiny neurons (MSNs) in the striatum are required for interval timing, or the estimation of the time over several seconds via a motor response. We and others have shown that striatal MSNs can encode the duration of temporal intervals via time-dependent ramping activity, progressive monotonic changes in firing rate preceding behaviorally salient points in time. Here, we investigated how timing-related activity within striatal ensembles changes with experience. We leveraged a rodent-optimized interval timing task in which mice ‘switch’ response ports after an amount of time has passed without reward. We report three main results. First, we found that the proportion of MSNs exhibiting time-dependent modulations of firing rate increased after 10 days of task overtraining. Second, temporal decoding by MSN ensembles increased with experience and was largely driven by time-related ramping activity. Finally, we found that time-related ramping activity generalized across both correct and error trials. These results enhance our understanding of striatal temporal processing by demonstrating that time-dependent activity within MSN ensembles evolves with experience and is dissociable from motor- and reward-related processes.
What about antibiotics for the treatment of the dyskinesia induced by L-DOPA?
L-DOPA-induced dyskinesia is a debilitating adverse effect of treating Parkinson’s disease with this drug. New therapeutic approaches that prevent or attenuate this side effect is clearly needed. Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesions were treated with L-DOPA (oral or subcutaneous, 20 mg kg-1) once a day for 14 days. After this period, we tested if doxycycline (40 mg kg-1, intraperitoneal, a subantimicrobial dose) and COL-3 (50 and 100 nmol, intracerebroventricular) could reverse LID. In an additional experiment, doxycycline was also administered repeatedly with L-DOPA to verify if it would prevent LID development. A single injection of doxycycline or COL-3 together with L-DOPA attenuated the dyskinesia. Co-treatment with doxycycline from the first day of L-DOPA suppressed the onset of dyskinesia. The improved motor responses to L-DOPA remained intact in the presence of doxycycline or COL-3, indicating the preservation of L-DOPA-produced benefits. Doxycycline treatment was associated with decreased immunoreactivity of FosB, cyclooxygenase-2, the astroglial protein GFAP and the microglial protein OX-42 which are elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline also decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and reactive oxygen species production. Metalloproteinase-2/-9 activity and production of reactive oxygen species in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia. The present study demonstrates the anti-dyskinetic potential of doxycycline and its analog compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or to prevent L-DOPA-induced dyskinesia in Parkinson’s patients.
Neurotoxicity is a major health problem in Africa: focus on Parkinson's / Parkinsonism
Parkinson's disease (PD) is the second most present neurodegenerative disease in the world after Alzheimer's. It is due to the progressive and irreversible loss of dopaminergic neurons of the substantia nigra Pars Compacta. Alpha synuclein deposits and the appearance of Lewi bodies are systematically associated with it. PD is characterized by four cardinal motor symptoms: bradykinesia / akinesia, rigidity, postural instability and tremors at rest. These symptoms appear when 80% of the dopaminergic endings disappear in the striatum. According to Braak's theory, non-motor symptoms appear much earlier and this is particularly the case with anxiety, depression, anhedonia, and sleep disturbances. In 90 to 95% of cases, the causes of the appearance of the disease remain unknown, but polluting toxic molecules are incriminated more and more. In Africa, neurodegenerative diseases of the Parkinson's type are increasingly present and a parallel seems to exist between the increase in cases and the presence of toxic and polluting products such as metals. My Web conference will focus on this aspect, i.e. present experimental arguments which reinforce the hypothesis of the incrimination of these pollutants in the incidence of Parkinson's disease and / or Parkinsonism. Among the lines of research that we have developed in my laboratory in Rabat, Morocco, I have chosen this one knowing that many of our PhD students and IBRO Alumni are working or trying to develop scientific research on neurotoxicity in correlation with pathologies of the brain.
The Dopamine Synapse and Learning
The actions of dopamine within the striatum are central to the selection of cortical and perhaps thalamic inputs that mediate learning throughout life, including during operant conditioning, reward and avoidance learning and the establishment of motor patterns. Dysfunction of these synaptic circuits during maturation or aging underlies many neurological, psychiatric and neurodevelopment disorders. We will discuss the biological sequences by which these synapses are altered as an animal interacts with the environment.
Male songbirds turn off their self-evaluation systems when they sing to females
Attending to mistakes while practicing alone provides opportunities for learning but self-evaluation during audience-directed performance could distract from ongoing execution. It remains unknown how animals switch between practice and performance modes, and how evaluation systems process errors across distinct performance contexts. We recorded from striatal-projecting dopamine (DA) neurons as male songbirds transitioned from singing alone to singing female-directed courtship song. In the presence of the female, singing-related performance error signals were reduced or gated off and DA neurons were instead phasically activated by female vocalizations. Mesostriatal DA neurons can thus dynamically change their tuning with changes in social context.