Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex

• Published in: Neuropharmacology Vol. 108; pp. 91 - 102
• Main Authors: Jiménez-Sánchez, Laura, Linge, Raquel, Campa, Leticia, Valdizán, Elsa M., Pazos, Ángel, Díaz, Álvaro, Adell, Albert
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2016
• Subjects: Animals; Antidepressant; Brain-Derived Neurotrophic Factor - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Deep brain stimulation; Deep Brain Stimulation - methods; Depression - metabolism; Depression - surgery; Glutamate; Interpersonal Relations; Male; Olfactory Bulb - chemistry; Olfactory Bulb - metabolism; Olfactory Bulb - surgery; Olfactory bulbectomy; Prefrontal Cortex - chemistry; Prefrontal Cortex - metabolism; Prefrontal Cortex - surgery; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Serotonin; Antidepressant; Serotonin; Olfactory bulbectomy; Glutamate; Deep brain stimulation
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.04.020

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. •DBS of the infralimbic cortex evoked antidepressant-like activity in both sham-operated and olfactory bulbectomized rats.•These effects occur with increased efflux of glutamate and serotonin, and protein levels of BDNF, Akt, CREB and GluA1.•The antidepressant-like action of DBS requires the activation of mTOR signaling pathway.•Changes in BDNF may underlie plasticity in brain areas relevant for depression such as prefrontal cortex and hippocampus.