Juan Mena Segovia

The principles of operation of subcortical neuronal networks and their interaction with neuromodulatory systems.​

Dr Juan Mena Segovia, MD, PhD is an expert in the principles of operation of subcortical networks and their interaction with neuromodulatory systems.

Neuromodulatory mechanisms underlying brain dynamics and behavior

The survival of an organism in its environment is determined by its ability to transform sensory information into action. In doing this transformation, a series of neuronal circuits become functionally correlated to compute distinct plausible outcomes and then choose one that offers the highest probability of goal success. This complex interplay between circuits is facilitated by the activity of subsets of neurons with long axonal projections that release so-called neuromodulators, i.e., molecules able to modify the electrical properties of neurons and their synaptic connections, and to override the functional connectivity of entire neuronal networks. Thus, neuromodulatory neurons form structural and functional nodes where multiple afferent systems converge, allowing them to integrate sensory information and internal representations originated from cortical and subcortical structures. In turn, they provide an output that synchronizes the computations of their target neurons over large brain areas and, as a consequence, determine the emergence of global brain states.

Our lab is interested in bridging the large-scale neuronal dynamics induced by neuromodulatory systems with their anatomical and molecular substrates (connectome), using a variety of techniques that include ultrastructural anatomy, neuronal tracing, in vivo juxtacellular and high-density electrophysiological recordings, optogenetics, pharmacogenetics and behavior. We aim to understand the principles of operation of neuromodulatory systems in health and disease, and their effects upon cortical and subcortical targets at the cellular, circuit and behavioral levels.

Our research program is divided in three major themes:

1) Mechanisms behind global network state transitions and the dynamics of arousal

Arousal is a state of brain activity that is critical for behavior. It is shaped by the activity of distinct types of subcortical neuromodulatory neurons acting in concert, including cholinergic, noradrenergic, serotonergic and dopaminergic subgroups, among others. Together or separately, and according to the behavioral context, they set the tone required for effective transmission of information across neuronal ensembles, synchronizing brain areas that have a common functional association. Such interactions may occur in specific ranges of frequency oscillations and lead to global network state transitions or microstates, the latter occurring during both the waking state and sleep. This mode of operation may be interpreted as a gating mechanism, whereby behaviorally-relevant information is enhanced and integrated across the appropriate channels. We are interested in characterizing the firing properties of neuromodulatory neurons across different global network states, in identifying the mechanisms that determine their activation, and in elucidating their impact on cortical dynamics and the sleep-wake cycle.

2) Subcortical integration of neuromodulatory mechanisms

Learning and acquisition of new behaviors rely on the physiological context in which new information is processed. Neuromodulators play a permissive role by regulating the behavioral state and by facilitating the computations in neurons organized in functional ensembles across large, integrated brain areas. One such area is the striatum, involved in reward-oriented learning and action selection (i.e., the promotion of preferred actions over undesired or competing actions). The activity of striatal neurons is dependent on glutamatergic afferent transmission (mainly from cortex and thalamus) timed with the dopaminergic input that promotes synaptic integration (arising in the ventral tegmental area, [VTA] and the substantia nigra pars compacta, [SNpc]). Importantly, the activity of thalamic and dopaminergic neurons are modulated by cholinergic terminals originating in the brainstem (pedunculopontine nucleus, PPN and laterodorsal tegmental nucleus, LDT), suggesting that cholinergic neurons are capable of modulating the coincident thalamic and dopaminergic inputs at the level of striatal microcircuits. We investigate the structural and functional organization in these pathways, the neuronal dynamics underlying the encoding of behaviorally-relevant (sensory) information (i.e. learning) into patterns of activity that will determine an outcome (i.e. action), and how different levels of arousal determine the optimization of neuronal computations and consequently the behavioral outcome.

3) Identifying the neuromodulatory basis of neuropsychiatric disorders

Some of the central features in the pathophysiology of common chronic neurological and psychiatric disorders involve the dysfunction or degeneration of specific neuromodulatory neurons that innervate wide areas of the brain (e.g., dopamine depletion in Parkinson’s disease and dopamine dysregulation in schizophrenia and drug-addiction; cholinergic depletion in Alzheimer’s disease, Progressive Supranuclear palsy, and some forms of dementia; serotonin dysfunction in depression, etc). While the etiology of these disorders is often associated with an alteration in the balance of neurotransmission, they develop into multi-system conditions with multiple symptoms, and are aggravated by the prolonged course of the disease. As such, following the degeneration or dysfunction of a neuromodulatory neuronal population, many of the current clinical efforts are oriented towards balancing the consequent aberrant activity in the brain that is at least partially produced by compensatory mechanisms. The knowledge of the specific neuronal elements of the network that are affected by these changes would offer a more specific strategy to overcome the impaired activity in neurological disorders, which could only be obtained by the use of animal models of human disease. Our lab studies the aberrant activity across subcortical circuits following the manipulation of neuromodulatory neurons (dopaminergic and cholinergic) that mimic neuropsychiatric disorders and aims to identify the most critical elements involved in the pathophysiological changes that determine aberrant network states in order to target such elements experimentally and revert the pathological state, thus providing clues to treat conditions in human disease.