Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed 1 week of recovery, following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.

Download Full-text

Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Rats

10.1101/2021.03.16.435686 ◽

2021 ◽

Author(s):

Nawshaba Nawreen ◽

Mark L Baccei ◽

James P Herman

Keyword(s):

Prefrontal Cortex ◽

Traumatic Stress ◽

Pyramidal Neurons ◽

Brain Slices ◽

Intrinsic Excitability ◽

Repetitive Firing ◽

Membrane Excitability ◽

Single Prolonged Stress ◽

Prolonged Stress ◽

Synaptic Drive

ABSTRACTPost-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed one week of recovery following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.Graphical AbstractSPS causes a decrease in excitatory synaptic drive and intrinsic excitability of IL pyramidal neurons.

Download Full-text

Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.780326 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lucas Canto-de-Souza ◽

Peyton G. Demetrovich ◽

Samantha Plas ◽

Rimenez R. Souza ◽

Joseph Epperson ◽

...

Keyword(s):

Prefrontal Cortex ◽

Incubation Period ◽

Conditioned Fear ◽

Male Rats ◽

Traumatic Experiences ◽

Post Traumatic Stress ◽

Single Prolonged Stress ◽

Optogenetic Stimulation ◽

Prolonged Stress ◽

Stimulation Of

Post-traumatic stress disorder (PTSD) is associated with decreased activity in the prefrontal cortex. PTSD-like pathophysiology and behaviors have been observed in rodents exposed to a single prolonged stress (SPS) procedure. When animals are left alone for 7 days after SPS treatment, they show increased anxiety-like behavior and impaired extinction of conditioned fear, and reduced activity in the prefrontal cortex. Here, we tested the hypothesis that daily optogenetic stimulation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) during the 7 days after SPS would reverse SPS effects on anxiety and fear extinction. Male Sprague-Dawley rats underwent SPS and then received daily optogenetic stimulation (20 Hz, 2 s trains, every 10 s for 15 min/day) of glutamatergic neurons of the left or right IL for seven days. After this incubation period, rats were tested in the elevated plus-maze (EPM). Twenty-four hours after the EPM test, rats underwent auditory fear conditioning (AFC), extinction training and a retention test. SPS increased anxiety-like behavior in the EPM task and produced a profound impairment in extinction of AFC. Optogenetic stimulation of the left IL, but not right, during the 7-day incubation period reversed the extinction impairment. Optogenetic stimulation did not reverse the increased anxiety-like behavior, suggesting that the extinction effects are not due to a treatment-induced reduction in anxiety. Results indicate that increased activity of the left IL after traumatic experiences can prevent development of extinction impairments. These findings suggest that non-invasive brain stimulation may be a useful tool for preventing maladaptive responses to trauma.

Download Full-text

Early Intervention With Intranasal NPY Prevents Single Prolonged Stress-Triggered Impairments in Hypothalamus and Ventral Hippocampus in Male Rats

Endocrinology ◽

10.1210/en.2014-1192 ◽

2014 ◽

Vol 155 (10) ◽

pp. 3920-3933 ◽

Cited By ~ 48

Author(s):

Marcela Laukova ◽

Lishay G. Alaluf ◽

Lidia I. Serova ◽

Victoria Arango ◽

Esther L. Sabban

Keyword(s):

Early Intervention ◽

Hpa Axis ◽

Traumatic Stress ◽

Feedback Inhibition ◽

Neuropsychiatric Symptoms ◽

Ventral Hippocampus ◽

Male Rats ◽

Nuclear Fraction ◽

Single Prolonged Stress ◽

Prolonged Stress

Abstract Intranasal administration of neuropeptide Y (NPY) is a promising treatment strategy to reduce traumatic stress-induced neuropsychiatric symptoms of posttraumatic stress disorder (PTSD). We evaluated the potential of intranasal NPY to prevent dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, a core neuroendocrine feature of PTSD. Rats were exposed to single prolonged stress (SPS), a PTSD animal model, and infused intranasally with vehicle or NPY immediately after SPS stressors. After 7 days undisturbed, hypothalamus and hippocampus, 2 structures regulating the HPA axis activity, were examined for changes in glucocorticoid receptor (GR) and CRH expression. Plasma ACTH and corticosterone, and hypothalamic CRH mRNA, were significantly higher in the vehicle but not NPY-treated group, compared with unstressed controls. Although total GR levels were not altered in hypothalamus, a significant decrease of GR phosphorylated on Ser232 and increased FK506-binding protein 5 mRNA were observed with the vehicle but not in animals infused with intranasal NPY. In contrast, in the ventral hippocampus, only vehicle-treated animals demonstrated elevated GR protein expression and increased GR phosphorylation on Ser232, specifically in the nuclear fraction. Additionally, SPS-induced increase of CRH mRNA in the ventral hippocampus was accompanied by apparent decrease of CRH peptide particularly in the CA3 subfield, both prevented by NPY. The results show that early intervention with intranasal NPY can prevent traumatic stress-triggered dysregulation of the HPA axis likely by restoring HPA axis proper negative feedback inhibition via GR. Thus, intranasal NPY has a potential as a noninvasive therapy to prevent negative effects of traumatic stress.

Download Full-text