Biology subjects

Huerta-Ocampo, I.

Publications and source records attributed to Huerta-Ocampo, I..

4 recordsLinked to original sources

bioRxiv2024

Optimized AAV capsids for diseases of the basal ganglia show robust potency and distribution in adult nonhuman primates

Huntingtons disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Additionally, for adeno-associated viruses (AAVs) intravascular delivery exposes peripheral tissues to the vast majority of the therapy, increasing the risk of immune responses and the quantity and associated cost of goods required for therapeutically relevant brain penetration levels. Here, we found that low dose, low volume delivery of unbiased AAV libraries into a focused brain region allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies at doses orders of magnitude lower than used in current clinical trials. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and also potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.

neuroscience↗

bioRxiv2022

Selective inhibition of goal-directed actions in the mesencephalic locomotor region

Dopamine enables purposive behavior and adjusts vigor as a function of the relative value of actions. In Parkinsons disease, dopamine neurons die and give rise to a series of motor and cognitive changes that interfere with the expression of volitional actions. Here we report a novel inhibitory input to dopamine neurons originated in the mesencephalic locomotor region that selectively blocks purposive behavior. GABAergic neurons of the pedunculopontine nucleus (PPN) synapse onto dopamine neurons of the substantia nigra and decrease dopamine release in the dorsal striatum. Activation of PPN neurons abolished exploratory locomotion and goal-directed actions while preserved other motor behaviors; furthermore, PPN caused a decrease in movement vigor and interrupted motor sequences presumably by modulating the immediate value of the learned action. Our results reveal an inhibitory mechanism in the midbrain that rapidly and reversibly adjusts the intrinsic value of ongoing actions.

neuroscience↗

bioRxiv2020

Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region. Here we characterize the whole-brain input connectome to cholinergic neurons across distinct functional domains (i.e. PPN vs LDT) using conditional transsynaptic retrograde labeling in ChAT::Cre male and female rats. The quantification of input neurons revealed that both PPN and LDT receive similar substantial inputs from the superior colliculus and the output of the basal ganglia (i.e. substantia nigra pars reticulata). In addition, we found that PPN cholinergic neurons receive preferential inputs from basal ganglia structures than from the cortex, whereas LDT cholinergic neurons receive preferential inputs from cortical areas. Our results provide the first characterization of inputs to PPN and LDT cholinergic neurons. The differences in afferents to each cholinergic structure support their differential roles in behavior. Significance statementAcetylcholine is a widespread neuromodulator that regulates a wide variety of functions including learning, goal-directed behavior and execution of movements. In this study we characterized the distribution of presynaptic neurons that modulate the activity of functionally distinct midbrain cholinergic neurons located in the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) by using a transsynaptic, modified-rabies virus strategy. We reveal that input neurons are widely distributed throughout the brain but segregated into specific functional domains. Motor related areas innervate preferentially the PPN, whereas limbic related areas preferentially innervate the LDT. Our results suggest that input neurons located along distinct functional domains have differential impact over cholinergic midbrain regions.

neuroscience↗

bioRxiv2018

Cholinergic Midbrain Afferents Modulate Striatal Circuits and Shape Encoding of Action Control

Assimilation of novel strategies into a consolidated action repertoire is a crucial function for behavioral adaptation and cognitive flexibility. Acetylcholine in the striatum plays a pivotal role in such adaptation and its release has been causally associated with the activity of cholinergic interneurons. Here we show that the midbrain, a previously unknown source of acetylcholine in the striatum, is a major contributor to cholinergic transmission in the striatal complex. Neurons of the pedunculopontine and laterodorsal tegmental nuclei synapse with striatal cholinergic interneurons and give rise to excitatory responses that, in turn, mediate inhibition of spiny projection neurons. Inhibition of acetylcholine release from midbrain terminals in the striatum impairs action shifting and mimics the effects observed following inhibition of acetylcholine release from striatal cholinergic interneurons. These results suggest the existence of two hierarchically-organized modes of cholinergic transmission in the striatum where cholinergic interneurons are modulated by cholinergic neurons of the midbrain.

neuroscience↗