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, among many others).

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.

 
Impaired functional connectivity between PPN and cortex in the Parkinsonian rat (see Valencia et al., 2013)

Impaired functional connectivity between PPN and cortex in the Parkinsonian rat (see Valencia et al., 2013)

 
 

Large-scale neuronal network dynamics in animal models of human disease involving neuromodulatory dysfunction

Dysfunction of dopaminergic and cholinergic systems causes some of the most devastating and costly diseases of the central nervous system. Because of the long-range connectivity of dopaminergic and cholinergic neurons, the effects of their depletion are widely observed; indeed, aberrant activity is also detected in systems that do not receive a direct connection from these neuromodulatory neurons, suggesting a series of compensatory mechanisms that appear along the progression of the disease. Recent theories propose the emergence of aberrant network states that affect the global functional connectivity, where different neuronal circuits would contribute to this pathological states differently. Detecting the neuronal substrate of the elements involved in these changes requires sampling over large brain areas with the capability of identifying their individual properties.

 

Reverting patterns of aberrant activity by manipulating specific subsets of neurons

The complexity of brain disorders has pushed the development of new research strategies focused on network-level approaches (e.g. genes, proteins, neuronal circuits). The identification of specific targets to revert an altered network state opens exceptional and far-reaching opportunities for novel therapeutic methods, but this requires extensive work at many experimental levels. We are particularly focused on the neuronal network consequences of dopamine and acetylcholine dysfunction, and the detection of the optimal neuronal targets for reverting the network activity back to its non-dysfunctional state.

 
Cell type-specific impairment of neuronal activity in the PPN in the Parkinsonian rat (see Martinez-Gonzalez et al., 2014)

Cell type-specific impairment of neuronal activity in the PPN in the Parkinsonian rat (see Martinez-Gonzalez et al., 2014)