Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex.
Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.
Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona (CSIC, IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
Laura
L
Jiménez-Sánchez
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), 39011 Santander, Spain.
Raquel
R
Linge
Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona (CSIC, IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
Leticia
L
Campa
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), 39011 Santander, Spain.
Elsa M
EM
Valdizán
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), 39011 Santander, Spain.
Ángel
Á
Pazos
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), 39011 Santander, Spain.
Álvaro
Á
Díaz
Departamento de Neuroquímica y Neurofarmacología, Instituto de Investigaciones Biomédicas de Barcelona (CSIC, IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (CSIC, Universidad de Cantabria), 39011 Santander, Spain. Electronic address: albert.adell@unican.es.
Albert
A
Adell
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D046690:Deep Brain Stimulation / Q000379:methods*; D003863:Depression / Q000378:metabolism* / Q000601:surgery; D007398:Interpersonal Relations; D008297:Male; D009830:Olfactory Bulb / Q000737:chemistry / Q000378:metabolism / Q000601:surgery; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000378:metabolism* / Q000601:surgery; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D051057:Proto-Oncogene Proteins c-akt
Antidepressant; Deep brain stimulation; Glutamate; Olfactory bulbectomy; Serotonin