Neural and behavioral bases of innate behaviors

Recently, ethological studies of animal behavior uncovered its complexity while neuroscientific work began unraveling the neural bases of behavior. Improvements in algorithmic understanding of behavior and neural function contributed to re- cent breakthroughs in robotics and artificial intelligence systems. Yet, animals’ decision-making and motor-control are unequalled by human engineered systems and the continued investigation of the behavioral and neural bases of these abilities is crucial for understanding brain function and inform further technological devel- opments. In my PhD work, I first investigate escape path selection in mice presented with threat, demonstrating how mice combined rapidly acquired spatial knowledge with an innate choice heuristic to inform decision-making. This strategy minimizes the requirement for trial-and-error learning and yields accurate decision-making by combining knowledge acquired at an evolutionarily time-scale with that acquired by the individual. Future work aimed at understanding how these sources of in- formation are combined in the brain to inform decision-making may lead to more efficient artificial learning agents. Next, I studied goal-directed locomotion behav- ior in which mice move rapidly through an environment to reach a goal location. Successful goal-directed locomotion behavior requires substantial navigation and motor control skills and, additionally, sophisticated planning and control of move- ments while moving at high speed. Detailed behavioral quantification and compar- ison to a control-theoretic model demonstrated that mice do possess such planning skills, allowing them to execute rapid and efficient trajectories to a goal. Population- level extracellular recordings of neural activity during goal directed locomotion was also used to begin uncovering the neural bases of planning during locomotion. Altogether, my work combined accurate quantification of animal movements with the- oretical models of optimal behavior to understand behavior at a computation level, aiming to provide crucial information to inform future studies on the neural bases of innate behaviors and aid in the development of novel artificial learning system

Incremental embodied chaotic exploration of self-organized motor behaviors with proprioceptor adaptation

This paper presents a general and fully dynamic embodied artificial neural system, which incrementally explores and learns motor behaviors through an integrated combination of chaotic search and reflex learning. The former uses adaptive bifurcation to exploit the intrinsic chaotic dynamics arising from neuro-body-environment interactions, while the latter is based around proprioceptor adaptation. The overall iterative search process formed from this combination is shown to have a close relationship to evolutionary methods. The architecture developed here allows realtime goal-directed exploration and learning of the possible motor patterns (e.g., for locomotion) of embodied systems of arbitrary morphology. Examples of its successful application to a simple biomechanical model, a simulated swimming robot, and a simulated quadruped robot are given. The tractability of the biomechanical systems allows detailed analysis of the overall dynamics of the search process. This analysis sheds light on the strong parallels with evolutionary search

Brainstem circuits involved in skilled forelimb movements

Movement is the main output of the nervous system as well as the fundamental form of interaction animals have with their environment. Due to its function and scope, movement has to be characterized by both stability and flexibility. Such apparently conflicting attributes are reflected in the complex organization of the motor system, composed of a vast network of widely distributed circuits interacting with each other to generate an appropriate motor output. Different neuronal structures, located throughout the brain, are responsible for producing a broad spectrum of actions, ranging from simple locomotion to complex goal directed movements such as reaching for food or playing a musical instrument. The brainstem is one of such structures, holding considerable importance in the generation of the motor output, but also largely unexplored, due to its less-than-accessible anatomic location, functional intricacies and the lack of appropriate techniques to investigate its complexity. Despite recent advances, a deeper understanding of the role of brainstem neuronal circuits in skilled movements is still missing. In this dissertation, we investigated the involvement of the lateral rostral medulla (LatRM) in the construction of skilled forelimb behaviors. The focus of my work was centered on elucidating the anatomical and functional relationships between LatRM and the caudal brainstem, and specifically on the interactions with the medullary reticular formation, considering both its ventral (MdV) and dorsal subdivisions (MdD). In summary, we reveal the existence of anatomically segregated subpopulations of neurons in the lower brainstem which encode different aspects of skilled forelimb movements. Moreover, we show that LatRM neurons are necessary for the correct execution of skilled motor programs and their activation produces complex coordinated actions. All this evidence suggests that LatRM may be a key orchestrator for skilled movements by functioning as integration center for upstream signals as well as coordinator by selecting the appropriate effectors in the lower medulla and the spinal cord

Molecular psychiatry of zebrafish

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research

Motor control in zebrafish : excitatory drive and developmental changes

An essential characteristic of human and animal life is the ability to move from one place to another, in order to survive in a complex environment. All the different forms of locomotion, like walking, swimming, crawling and flying, have one common feature: rhythmic and alternating movements of the body. These movements are generated by neuronal networks in the spinal cord. The overall aim of this thesis is to investigate the mechanisms underlying locomotion in zebrafish, with particular focus on excitatory drive and developmental changes. Excitatory interneurons are believed to represent the core components for the generation of the locomotor rhythm, since they drive both inhibitory interneurons and motoneurons. By ablating one specific group of interneurons, the V2a interneurons, we show that they represent an intrinsic source of excitation necessary for the normal expression of the locomotor rhythm. Ablation of V2a interneurons results in an increase in the threshold to induce swimming and a decrease in swimming frequency and episode duration. To demonstrate that the excitatory drive from ipsilateral premotor V2a interneurons is also sufficient to drive swimming, we used optogenetics to activate the V2a interneurons specifically. Upon illumination, V2a interneurons displayed rhythmic oscillations that resembled the typical beat-and-glide swimming. Peripheral nerve recordings confirmed that the bursting activity in single neurons corresponds to swimming activity, which is characterized by left-right-alternation and rostrocaudal delay. This indicates that swimming activity emerges from the activity of an underlying V2a interneuron network. The third aim of this thesis is to reveal the developmental changes of the swimming pattern and the motoneuron properties. By systematically recording peripheral nerve activity and primary motoneuron properties during different developmental stages, we were able to define the time frame of the switch in swimming behavior from larval episodic to adult continuous swimming to 4-5 weeks post fertilization. Primary motoneurons stop participating in swimming within the same time window and are from around 6 weeks onward only active during escape behavior. In conclusion, we show that the excitatory V2a interneurons in zebrafish are necessary and sufficient for the rhythm generating network to generate a coordinated swimming motor pattern and that there is a major switch in the locomotor pattern and primary motoneuron recruitment around 4-5 weeks of development

Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons

Single-cell RNA sequencing (RNA-Seq) provides rich information about cell types and states. However, it is difficult to capture rare dynamic processes, such as adult neurogenesis, because isolation of rare neurons from adult tissue is challenging and markers for each phase are limited. Here, we develop Div-Seq, which combines scalable single-nucleus RNA-Seq (sNuc-Seq) with pulse labeling of proliferating cells by 5-ethynyl-2′-deoxyuridine (EdU) to profile individual dividing cells. sNuc-Seq and Div-Seq can sensitively identify closely related hippocampal cell types and track transcriptional dynamics of newborn neurons within the adult hippocampal neurogenic niche, respectively. We also apply Div-Seq to identify and profile rare newborn neurons in the adult spinal cord, a noncanonical neurogenic region. sNuc-Seq and Div-Seq open the way for unbiased analysis of diverse complex tissues.National Institute of Mental Health (U.S.) (Grant U01MH105960)National Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)National Institute of Mental Health (U.S.) (Grant 1R01-MH110049

Progesterone reduces secondary damage, preserves white matter and improves locomotor outcome after spinal cord contusion

Progesterone is an anti-inflammatory and promyelinating agent after spinal cord injury, but its effectiveness on functional recovery is still controversial. In the current study, we tested the effects of chronic progesterone administration on tissue preservation and functional recovery in a clinically relevant model of spinal cord lesion (thoracic contusion). Using magnetic resonance imaging, we observed that progesterone reduced both volume and rostrocaudal extension of the lesion at 60 days post-injury. In addition, progesterone increased the number of total mature oligodendrocytes, myelin basic protein immunoreactivity, and the number of axonal profiles at the epicenter of the lesion. Further, progesterone treatment significantly improved motor outcome as assessed using the Basso-Bresnahan-Beattie scale for locomotion and CatWalk gait analysis. These data suggest that progesterone could be considered a promising therapeutical candidate for spinal cord injury.Fil: Garcia Ovejero, Daniel. Hospital Nacional de Paraplejicos; EspañaFil: Gonzalez, Susana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Paniagua Torija, Beatriz. Hospital Nacional de Paraplejicos; EspañaFil: Lima, Analia Ethel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Molina Holgado, Eduardo. Hospital Nacional de Paraplejicos; EspañaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Knocking at the brain’s door: intravital two-photon imaging of autoreactive T cell interactions with CNS structures

Since the first applications of two-photon microscopy in immunology 10 years ago, the number of studies using this advanced technology has increased dramatically. The two-photon microscope allows long-term visualization of cell motility in the living tissue with minimal phototoxicity. Using this technique, we examined brain autoantigen-specific T cell behavior in experimental autoimmune encephalitomyelitis, the animal model of human multiple sclerosis. Even before disease symptoms appear, the autoreactive T cells arrive at their target organ. There they crawl along the intraluminal surface of central nervous system (CNS) blood vessels before they extravasate. In the perivascular environment, the T cells meet phagocytes that present autoantigens. This contact activates the T cells to penetrate deep into the CNS parenchyma, where the infiltrated T cells again can find antigen, be further activated, and produce cytokines, resulting in massive immune cell recruitment and clinical disease

Neuronal Wiring: Linking Dendrite Placement to Synapse Formation

SummaryUnderstanding the processes that drive the formation of synapses between specific neurons within a circuit is critical to understanding how neural networks develop. A new study of synapse formation between motor neurons and pre-synaptic partners highlights the importance of dendrite placement