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The impact of stress on the dopamine system depends on the state of the critical period of neuroplasticity: implications for depression and schizophrenia and for the study of new drug targets

Grant number: 18/17597-3
Support type:Research Grants - Young Investigators Grants
Duration: October 01, 2019 - September 30, 2024
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Felipe Villela Gomes
Grantee:Felipe Villela Gomes
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Alline Cristina de Campos ; Anthony A. Grace ; Elaine Aparecida Del Bel Belluz Guimarães ; Francisco Silveira Guimaraes

Abstract

In addition to sharing the exposure to stressful events as a common risk factor, depression and schizophrenia also share many of the genetic variations associated with these psychiatric disorders. However, they differ in the mean age of diagnosis. While schizophrenia is usually diagnosed in late adolescence/early adulthood (18-25 years), depression seems to be more common in adults (25-45 years). These pieces of evidence point to an intriguing possibility: socio-environmental factors, such as stress exposure, may be common risk factors for the development of these disorders, but with the age of exposure determining the possible consequence. This may be related to the critical period of neuroplasticity, mainly due to a greater susceptibility of GABAergic interneurons containing parvalbumin (PV) during this period, which extends until the onset of adulthood. PV interneurons play an important role in regulating the synchronized activity of GABAergic interneurons and glutamatergic pyramidal neurons (excitatory-inhibitory balance). In both depression and schizophrenia, a hyperactivity of afferent structures that regulate the dopaminergic system in the ventral tegmental area (VTA), such as the prefrontal cortex (PFC), ventral hippocampus (vHip) and amygdala, has been associated with changes in the excitatory-inhibitory balance mediated by PV interneuron dysfunction. In schizophrenia, a hyperactivity of the ventral hippocampus has been associated with a hyperdopaminergic state. On the other hand, a hypodopaminergic state which has been associated with depression result from a hyperactivity of both the infra-limbic portion of the PFC and the basolateral amygdala. In addition, the nature of the changes in PV interneurons differs in these disorders. In schizophrenia, there is a change in the function of PV interneurons in PFC and vHip, as well as loss of these cells in vHip. In depression, there is only a change in the activity of the cortical PV interneurons, but without cell loss. Thus, the central hypothesis of this proposal is that exposure to stress during critical periods of neuroplasticity, such as adolescence, could result in a loss in the number and in the function of PV interneurons and, thus, it favors the development of schizophrenia. However, if the individual is "protected" during this time of greater vulnerability of PV interneurons, but experiences exposure to stress later in life, this could determine the development of depression. Therefore, the age at which stress exposure occurs would determine the pathology present in the adult. Thus, in this proposal we hope to investigate the (1) behavioral and electrophysiological changes of dopamine neurons in the VTA induced by exposure to stress during different ages (juvenile and adult period); (2) the relationship between behavioral/electrophysiological changes with the formation/development of PV interneurons; (3) the brain circuits involved in the changes in dopamine neuron activity in the VTA after exposure to stress; (4) the impact of the critical period of neuroplasticity on stress susceptibility by examining whether reopening of the critical period in the adult animal could recreate an adolescent phenotype by increasing the vulnerability of the PV interneurons to the effects of stress. Additionally, another hypothesis to be tested is (5) that drugs with a potential to attenuate the loss of PV interneurons, as well as the functional changes in the excitatory-inhibitory balance induced by stress, may be alternatives for the treatment of depression and schizophrenia. (AU)