The present study elucidated whether early life stress alters the extracellular signal-regulated kinase (ERK) pathway that underlies fear retrieval and fear extinction based on a contextual fear conditioning paradigm, using a juvenile stress model. Levels of phospho-ERK (pERK), the active form of ERK, increased after fear retrieval in the hippocampal CA1 region but not in the medial prefrontal cortex (mPFC). ERK activation in the CA1 following fear retrieval was not observed in adult rats who received aversive footshock (FS) stimuli during the second postnatal period (2wFS), which exhibited low levels of freezing. In fear extinction, pERK levels in the CA1 were increased by repeated extinction trials, but they were not altered after extinction retrieval. In contrast, pERK levels in the mPFC did not change during extinction training, but were enhanced after extinction retrieval. These findings were compatible in part with electrophysiological data showing that synaptic transmission in the CA1 field and mPFC was enhanced during extinction training and extinction retrieval, respectively. ERK activation in the CA1 and mPFC associated with extinction processes did not occur in rats that received FS stimuli during the third postnatal period (3wFS), which exhibited sustained freezing behavior. The repressed ERK signaling and extinction deficit observed in the 3wFS group were ameliorated by treatment with the partial N-methyl-D-aspartate receptor agonist D-cycloserine. These findings suggest that early postnatal stress induced the downregulation of ERK signaling in distinct brain regions through region-specific regulation, which may lead to increased behavioral abnormalities or emotional vulnerabilities in adulthood.
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder accompanied by cognitive and learning deficits, which is prevalent among boys. Juvenile male stroke-prone spontaneously hypertensive rats (SHRSP) exhibit ADHD-like behaviors including cognitive deficits and represent one animal model of ADHD. Here, we define a mechanism underlying cognitive dysfunction observed in SHRSP. Acute methylphenidate (MPH: 1mg/kg, p.o.) administration to SHRSP significantly improved not only inattention in a Y-maze task but also cognitive dysfunction in a novel object recognition test. Interestingly, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, which is essential for memory and learning acquisition, was excessively elevated in the medial prefrontal cortex (mPFC) but not in the hippocampal CA1 region of SHRSP compared with Wistar-Kyoto (WKY) rats. We also confirmed that elevated CaMKII autophosphorylation in the mPFC causes increased phosphorylation of the CaMKII substrate α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser-831). Ca(2+)-dependent phosphorylation levels of factors such as extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) were unchanged in the SHRSP mPFC. Also, protein levels of the dopamine D2 receptor (D2R) but not the dopamine D1 receptor (D1R) were increased in the SHRSP mPFC. Acute MPH (1mg/kg, p.o.) administration attenuated aberrant CaMKII activity and increased GluR1 phosphorylation observed in SHRSP. Taken together, we propose that cognitive impairment in SHRSP is associated with aberrant CaMKII activity in the mPFC.
Fear extinction-based exposure treatment is an important component of psychotherapy for anxiety disorders such as posttraumatic stress disorder (PTSD). Recent studies have focused on pharmacological approaches combined with exposure therapy to augment extinction. In this study, we elucidated the therapeutic potential of the serotonin 1A (5-HT(1A) ) receptor agonist tandospirone compared with the effects of the N-methyl-D-aspartate partial agonist D-cycloserine (DCS), focusing on the possible involvement of dopaminergic mechanisms. We used a rat model of juvenile stress [aversive footshock (FS)] exposure during the third postnatal week (3wFS). The 3wFS group exhibited extinction deficit reflected in sustained fear-related behavior and synaptic dysfunction in the hippocampal CA1 field and medial prefrontal cortex (mPFC), which are responsible for extinction processes. Tandospirone administration (5 mg/kg, i.p.) before and after the extinction trials ameliorated both the behavioral deficit and synaptic dysfunction, i.e., synaptic efficacy in the CA1 field and mPFC associated with extinction training and retrieval, respectively, was potentiated in the tandospirone-treated 3wFS group. Extracellular dopamine release in the mPFC was increased by extinction retrieval in the non-FS control group. This facilitation was not observed in the 3wFS group; however, tandospirone treatment increased cortical dopamine levels after extinction retrieval. DCS (15 mg/kg, i.p.) also ameliorated the extinction deficit in the 3wFS group, but impaired extinction in the non-FS control group. These results suggest that tandospirone has therapeutic potential for enhancing synaptic efficacy associated with extinction processes by involving dopaminergic mechanisms. Pharmacological agents that target cortical dopaminergic systems may provide new insights into the development of therapeutic treatments of anxiety disorders, including PTSD.
Abstract. Gender differences in psychiatric disorders are considered to be associated with the serotonergic (5-HTergic) system; however the underlying mechanisms have not been clearly elucidated. In this study, possible involvement of the median raphe nucleus (MRN)-hippocampus 5-HTergic system in gender-specific emotional regulation was investigated, focusing on synaptic plasticity in rats. A behavioral study using a contextual fear conditioning (CFC) paradigm showed that the females exhibited low anxiety-like behavior. Extracellular 5-HT levels in the hippocampus were increased by CFC only in the males. Long-term potentiation (LTP) in the hippocampal CA1 field was suppressed after CFC in the males, which was mimicked by the synaptic response to MRN electrical stimulation. In the MRN, 5-HT immunoreactive cells significantly increased in the females compared with those in the males. Pretreatment with the 5-HT 1A receptor agonists tandospirone (10 mg/kg, i.p.) and 8-OH DPAT (3 mg/kg, i.p.) significantly suppressed LTP induction in the males. Synaptic responses to CFC and 5-HT 1A receptor interventions were not observed in the females. These results suggest that the metaplastic 5-HTergic mechanism via 5-HT 1A receptors in the MRN-hippocampus pathway is a key component for gender-specific emotional regulation and may be a cause of psychiatric disorders associated with vulnerability or resistance to emotional stress.
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