BackgroundMemory consolidation, reconsolidation, and extinction have been shown to require new gene expression. Poly ADP-ribosylation mediated by poly (ADP-ribose) polymerase-1 (PARP-1) is known to regulate transcription through histone modification. Recent studies have suggested that PARP-1 positively regulates the formation of long-term memory (LTM); however, the roles of PARP-1 in memory processes, especially processes after retrieval, remain unknown.ResultsHere, we show critical roles for PARP-1 in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of PARP-1 activity in the hippocampus or medial prefrontal cortex (mPFC) on these memory processes. Similarly with previous findings, a micro-infusion of the PARP-1 inhibitor 3-aminobenzamide or PJ34 into the dorsal hippocampus, but not mPFC, impaired LTM formation without affecting short-term memory (STM). Importantly, this pharmacological blockade of PARP-1 in the dorsal hippocampus, but not mPFC, also disrupted post-reactivation LTM without affecting post-reactivation STM. Conversely, micro-infusion of the PARP-1 inhibitors into the mPFC, but not dorsal hippocampus, blocked long-term extinction. Additionally, systemic administration of the PARP-1 inhibitor Tiq-A blocked c-fos induction in the hippocampus, which is observed when memory is consolidated or reconsolidated, and also blocked c-fos induction in the mPFC, which is observed when memory is extinguished.ConclusionsOur observations showed that PARP-1 activation is required for the consolidation, reconsolidation, and extinction of contextual fear memory and suggested that PARP-1 contributes to the new gene expression necessary for these memory processes.

Perinatal exposure to epidermal growth factor (EGF) induces various cognitive and behavioral abnormalities after maturation in non-human animals, and is used for animal models of schizophrenia. Patients with schizophrenia often display a reduction of mismatch negativity (MMN), which is a stimulus-change specific event-related brain potential. Do the EGF model animals also exhibit the MMN reduction as schizophrenic patients do? This study addressed this question to verify the pathophysiological validity of this model. Neonatal rats received repeated administration of EGF or saline and were grown until adulthood. Employing the odd-ball paradigm of distinct tone pitches, tone-evoked electroencephalogram (EEG) components were recorded from electrodes on the auditory and frontal cortices of awake rats, referencing an electrode on the frontal sinus. The amplitude of the MMN-like potential was significantly reduced in EGF-treated rats compared with saline-injected control rats. The wavelet analysis of the EEG during a near period of tone stimulation revealed that synchronization of EEG activity, especially with beta and gamma bands, was reduced in EGF-treated rats. Results suggest that animals exposed to EGF during a perinatal period serve as a promising neurodevelopmental model of schizophrenia.

Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

Memory consolidation and reconsolidation have been shown to require new gene expression. N-glycosylation, one of the major post-translational modifications, is known to play essential or regulatory roles in protein function. A previous study suggested that N-glycosylation is required for the maintenance of long-term potentiation in hippocampal CA1 neurons. However, the role of de novo N-glycosylation in learning and memory, such as memory consolidation and reconsolidation, still remains unclear. Here, we show critical roles for N-glycosylation in the consolidation and reconsolidation of contextual fear memory in mice. We examined the effects of pharmacological inhibition of N-glycosylation in the hippocampus on these memory processes using three different inhibitors (tunicamycin, 1-deoxynojirimycin, and swainsonine) that block the enzymatic activity required for N-glycosylation at different steps. Microinfusions of the N-glycosylation inhibitors into the dorsal hippocampus impaired long-term memory (LTM) formation without affecting short-term memory (STM). Similarly, this pharmacological blockade of N-glycosylation in the dorsal hippocampus also disrupted post-reactivation LTM after retrieval without affecting post-reactivation STM. Additionally, a microinfusion of swainsonine blocked c-fos induction in the hippocampus, which is observed when memory is consolidated. Our observations showed that N-glycosylation is required for the consolidation and reconsolidation of contextual fear memory and suggested that N-glycosylation contributes to the new gene expression necessary for these memory processes.

Dopamine in the prefrontal cortex is essential for the regulation of social behavior. However, stress‐causing social withdrawal also promotes dopamine release in the prefrontal cortex. Thus, this evidence suggests opposite functions of dopamine in the prefrontal cortex. However, the influence of dopamine on prefrontal functions is yet to be fully understood. Here, we show that dopamine differentially modulated the neuronal activity triggered by social stimuli in the prefrontal cortex, depending on the duration of the dopamine activation (transient or sustained activation). Using chemogenetic techniques, we have found that social behavior was negatively regulated by a sustained increase in dopamine neuronal activity in the ventral tegmental area, while it was positively regulated by an acute increase. The duration of social interactions was positively correlated with the transient dopamine release triggered by social stimuli in the prefrontal cortex and negatively correlated with the sustained increase in prefrontal dopamine levels. Furthermore, the elevation of neural calcium signal, triggered by social stimuli, in the prefrontal cortex was attenuated by the persistent elevation of prefrontal dopamine levels, whereas an acute increase in dopamine levels enhanced it. Additionally, the chronic excess of dopamine suppressed c‐Fos induction triggered by social stimuli in prefrontal neurons expressing dopamine D1 receptors, but not D2 receptors. These results suggest that sustained activation of prefrontal dopamine, at the opposite of its transient activation, can reduce prefrontal activity associated with social behavior, even for identical dopamine concentrations. Thus, dopamine plays opposite roles in modulating prefrontal activity depending on the duration of its action.

Auditory neurophysiological responses, such as steady-state responses, event-related potential P300/P3, and phase-amplitude coupling, are promising translational biomarkers for schizophrenia, but their molecular underpinning is poorly understood. Focusing on ErbB receptor signals that are implicated in both schizophrenia and auditory processing/cognition, we explored the causal biological links between ErbB signals and these auditory traits with an experimental intervention into rats. We peripherally challenged rat pups with one of the amniotic ErbB ligands, epidermal growth factor (EGF), and characterized its consequence on the series of these auditory electrocorticographic measures. Auditory brainstem responses (ABRs) and cortical ON responses were also assessed under anesthesia to estimate the influence of higher brain regions. An auditory steady-state paradigm revealed attenuation of spectral power and phase synchrony to 40-Hz stimuli in EGF-challenged rats. We observed a reduction in duration mismatch negativity-like potentials and a delay of P3a responses, all of which are relevant to the reported auditory pathophysiological traits of patients with schizophrenia. Moreover, the perinatal EGF challenges resulted in enhanced theta-alpha/beta and theta-gamma coupling within the auditory cortex and changes in ABRs. However, the EGF challenges retained the normal ranges of cortical ON responses, potentially ruling out their fundamental auditory deficits. Perinatal exposure of an ErbB ligand to rats strikingly reproduced the whole series of aberrant auditory responses and oscillations previously reported in patients with schizophrenia. Accordingly, these findings suggest that developmental deficits in ErbB/EGF signaling might be involved in the auditory pathophysiology associated with schizophrenia.

Aims The brain function that detects deviations in the acoustic environment can be evaluated with mismatch negativity (MMN). MMN to sound duration deviance has recently drawn attention as a biomarker for schizophrenia. Nonhuman animals, including rats, also exhibit MMN‐like potentials. Therefore, MMN research in nonhuman animals can help to clarify the neural mechanisms underlying MMN production. However, results from preclinical MMN studies on duration deviance have been conflicting. We investigated the effect of sound frequency on MMN‐like potentials to duration deviance in rats. Methods Event‐related potentials were recorded from an electrode placed on the primary auditory cortex of free‐moving rats using an oddball paradigm consisting of 50‐ms duration tones (standards) and 150‐ms duration tones (deviants) at a 500‐ms stimulus onset asynchrony. The sound frequency was set to three conditions: 3, 12, and 50 kHz. Results MMN‐like potentials that depended on the short‐term stimulus history of background regularity were only observed in the 12‐kHz tone frequency condition. Conclusions MMN‐like potentials to duration deviance are subject to tone frequency of the oddball paradigm in rats, suggesting that rats have distinct sound duration recognition ability.

Genetic and environmental factors interact with each other to influence the risk of various psychiatric diseases; however, the intensity and nature of their interactions remain to be elucidated. We established a maternal infection model using polyinosinic‐polycytidylic acid (Poly(I:C)) to determine the relationship between the maternal breeding environment and behavioral changes in the offspring. We purchased pregnant C57BL/6J mice from three breeders and administered Poly(I:C) (2 mg/kg) intravenously in their tail vein on gestation day 15. The offspring were raised to 8‐12 weeks old and subjected to the acoustic startle tests to compare their startle response intensity, prepulse inhibition levels, and degree of the adaptation of the startle response. No statistical interaction between Poly(I:C) administration and sex was observed for prepulse inhibition; thus, male and female mice were analyzed together. There was a statistical interaction between the breeder origin of offspring and prepulse inhibition; the Poly(I:C) challenge significantly decreased prepulse inhibition levels of the offspring born to the pregnant dams from Breeder A but not those from the other breeders. However, we failed to detect significant inter‐breeder differences in Poly(I:C) effects on startle response and on startle adaptation with the given number of mice examined. The rearing environment of mouse dams has a prominent effect on the Poly(I:C)‐induced prepulse inhibition deficits in this maternal immune activation model.