Compensatory enhancement of paternal care in maternally neglected mice family.

Parental care strategies, ranging from biparental to uniparental, evolve based on factors affecting sexual conflict over care. Plasticity in how parents respond to reduction in each other's care effort is thus proposed to be important in the evolution of parental care behaviors. Models predict that 'obligate' biparental care is stable when a parent responds to reduced partner effort with 'partial' compensation, trading-off current and future reproduction. A meta-analysis of experimental studies on biparental birds also revealed partial compensation, supporting coevolution of parental care type and plasticity pattern. However, few studies have addressed this issue across different taxa and different parental care types. In laboratory mice, a female-biased 'facultative' biparental species, fathers paired with a competent mother rarely provide care. We show that, when mated with a pup-neglecting mutant mother, fathers increased care effort to 'fully' compensate for the lost maternal care in both pup survival rate and total care amount. Pup retrieval latency was significantly shorter, and neural activity in relevant brain regions twice as high, suggesting enhanced motivation. This study with mice not only opens a road to explore the neural correlates of paternal plasticity but will also help understand how behavioral plasticity contributes to adaptive evolution of parental care behaviors.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Abnormal maternal behavior in mice lacking phospholipase Cß1.

Motherhood goes through preparation, onset and maintenance phases until the natural weaning. A variety of changes in hormonal/neurohormonal systems and brain circuits are involved in the maternal behavior. Hormones, neuropeptides, and neurotransmitters involved in maternal behavior act via G-protein-coupled receptors, many of which in turn activate plasma membrane enzymes including phospholipase C (PLC) ß isoforms. In this study, we examined the effect of PLCß1 knockout (KO) on maternal behavior. There was little difference between PLCß1-KO and wild-type (WT) dams in the relative time spent in maternal behavior during the period between 24 h prepartum and 12 h postpartum (-24 h ∼ PPH 12). After PPH 18, however, PLCß1-KO dams neglected their pups so that they all died in 2-3 days. In the pup retrieval test, latency was not different during the period within PPH 12, but after PPH 18, PLCß1-KO dams could not finish pup retrieval in a given time. During both periods, FosB expression in the nucleus accumbens (NAcc) of PLCß1-KO dams was significantly lower than WT, but not different in the medial preoptic area (mPOA). Given that mPOA activity is required for initiation of maternal behavior, and that NAcc is known to be involved in maternal motivation and maintenance of maternal behavior, our results suggest that PLCß1 signaling is essential for transition from the onset to maintenance phase of maternal behavior.

Training-Dependent Change in Content of Association in Appetitive Pavlovian Conditioning.

In appetitive Pavlovian conditioning, experience with a conditional relationship between a cue [conditioned stimulus (CS)] and a reward [unconditioned stimulus (US)] bestows CS with the ability to promote adaptive behavior patterns. Different features of US (e.g., identity-specific sensory, general motivational) can be encoded by CS based on the nature of the CS-US relationship experienced (e.g., temporal factors such as training amount) and the content of association may determine the influence of CS over behavior (e.g., mediated learning, conditioned reinforcement). The content of association changed with varying conditioning factors, thereby altering behavioral consequences, however, has never been addressed in relevant brain signals evoked by CS. Our previous study found that phospholipase C ß1-knockout (PLCß1-KO) mice display persistent mediated learning over the extended course of odor-sugar conditioning, and that wild-type (WT) mice lose mediated learning sensitivity after extended training. In this study, in order to see whether this behavioral difference between these two genotypes comes from a difference in the course of association content, we examined whether odor CS can evoke the taste sensory representation of an absent sugar US after minimal- and extended training in these mice. In contrast to WT, which lost CS-evoked neural activation (c-Fos expression) in the gustatory cortex after extended training, KO mice displayed persistent association with the sensory feature of sugar, suggesting that sensory encoding is reliably linked to mediated learning sensitivity and there is a training-dependent change in the content of association in WT. PLCß1 knockdown in the left medial prefrontal cortex (mPFC) resulted in mediated learning sensitivity and CS-evoked gustatory cortical activation after extended training, proposing a molecular component of the neural system underlying this Pavlovian conditioning process. We also discuss how disruption of this process is implicated for hallucination-like behaviors (impaired reality testing).

Ccny knockout mice display an enhanced susceptibility to kainic acid-induced epilepsy.

Cyclin Y (CCNY) is a member of cyclin superfamily proteins involved in the regulation of the cell cycle in proliferating cells. Intriguingly, CCNY is highly expressed in terminally differentiated neuronal cells of multiple brain regions and acts as a postsynaptic protein, which plays an inhibitory role in long-term potentiation. However, the pathophysiological significance of CCNY in the nervous system remains largely unexplored. In this study, we revisited our RNA-sequencing (RNA-seq) data obtained from cultured hippocampal neurons virally overexpressing or depleting CCNY. Using RNA-seq-based bioinformatic disease analysis and synaptic gene ontology analysis, we identified that numerous genes associated with epilepsy (e.g. Chrna4, Gabrd, Nhlrc1, Reln, Samd12, Slc6a1, etc.) or neurodegenerative diseases (e.g. Psen1, Pdyn, Ndrg1, etc.) are affected by the level of CCNY expression. In agreement with the RNA-seq-based disease analysis, we found that Ccny knockout (KO) mice are more susceptible to kainic acid-induced epilepsy than wild-type mice. In addition, some epilepsy-associated genes that are regulated by CCNY levels were further validated in the brain of Ccny KO mice at the mRNA and protein levels. Collectively, our findings indicate that CCNY shifts the expression profile of epilepsy-associated genes and exerts a protective effect against kainic acid-induced epilepsy, suggesting CCNY as a potential pharmaceutical candidate for the treatment of epilepsy.

Dynamic Changes in the Bridging Collaterals of the Basal Ganglia Circuitry Control Stress-Related Behaviors in Mice.

The basal ganglia network has been implicated in the control of adaptive behavior, possibly by integrating motor learning and motivational processes. Both positive and negative reinforcement appear to shape our behavioral adaptation by modulating the function of the basal ganglia. Here, we examined a transgenic mouse line (G2CT) in which synaptic transmissions onto the medium spiny neurons (MSNs) of the basal ganglia are depressed. We found that the level of collaterals from direct pathway MSNs in the external segment of the globus pallidus (GPe) ('bridging collaterals') was decreased in these mice, and this was accompanied by behavioral inhibition under stress. Furthermore, additional manipulations that could further decrease or restore the level of the bridging collaterals resulted in an increase in behavioral inhibition or active behavior in the G2CT mice, respectively. Collectively, our data indicate that the striatum of the basal ganglia network integrates negative emotions and controls appropriate coping responses in which the bridging collateral connections in the GPe play a critical regulatory role.

Impaired Reality Testing in Mice Lacking Phospholipase Cß1: Observed by Persistent Representation-Mediated Taste Aversion.

Hallucinations and delusions are the most prominent symptoms of schizophrenia and characterized by impaired reality testing. Representation-mediated taste aversion (RMTA) has been proposed as a potential behavioral assessment of reality testing and has been applied to a neurodevelopmental rat model of schizophrenia. However, the theory underlying this approach has not been generalized yet with any demonstration of impaired reality testing in other animal models of schizophrenia, such as genetically-modified mice. We devised a RMTA procedure for mice that combines a Pavlovian association protocol pairing odor conditioned stimulus (CS) with sugar reward unconditioned stimulus (US), and a conditioned taste aversion (CTA) method. In this RMTA paradigm, we compared performances of wild-type (PLCß1+/+) mice and phospholipase C ß1 knock-out (PLCß1-/-) mice which are known as one of the genetic models for schizophrenia. With a minimal amount of initial odor-sugar associative training, both PLCß1+/+ and PLCß1-/- mice were able to form an aversion to the sugar reward when the odor CS predicting sugar was paired with nausea. With an extended initial training, however, only PLCß1-/- mice could form a RMTA. This persistent RMTA displayed by PLCß1-/- mice shows their inability to distinguish real sugar from the CS-evoked representation of sugar at a stage in associative learning where wild-type mice normally could differentiate the two. These results demonstrate an impaired reality testing first observed in a genetic mouse model of schizophrenia, and suggest that RMTA paradigm may, with general applicability, allow diverse biological approaches to impaired reality testing.

Knockdown of phospholipase C-ß1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes.

BACKGROUND: Decreased expression of phospholipase C-ß1 (PLC-ß1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-ß1 expression and the pathogenesis of schizophrenia. Although PLC-ß1-null (PLC-ß1(-/-)) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-ß1 expression in the brain contribute to specific behavioural defects. METHODS: We selectively knocked down PLC-ß1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice. RESULTS: Silencing PLC-ß1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophrenia-related behaviours observed in PLC-ß1-/- mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-ß1 knockdown mice. LIMITATIONS: Phenotypes of PLC-ß1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia. CONCLUSION: These results indicate that PLC-ß1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-ß1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.

Novel thienopyrimidinones as mGluR1 antagonists.

There has been much attention to discover mGluR1 antagonists for treating various central nervous system diseases such as seizures and neuropathic pain. Thienopyrimidinone derivatives were designed, synthesized, and biologically evaluated against mGluR1. Among the synthesized compounds, 3-(4-methoxyphenyl)-7-(o-tolyl)thienopyrimidin-4-one 30 exhibited the most potent inhibitory activity with an IC50 value of 45 nM and good selectivity over mGluR5. Also, the selective mGluR1 antagonist 30 showed marginal hERG channel activity (IC50 = 9.87 µM), good profiles to CYP isozymes, and a good pharmacokinetic profile. Overall, the compound 30 was identified as a selective mGluR1 antagonist with a good pharmacokinetic profile, which is probably devoid of cardiac side effect and drug-drug interactions. Therefore, the compound 30 can be expected to be broadly used as mGluR1 antagonistic chemical probe in in vitro and in vivo study for investigating CNS diseases.

Phospholipase C-ß1 and schizophrenia-related behaviors.

Abnormal expression patterns of phospholipase C-ß1(PLC-ß1) in specific brain areas of patients with schizophrenia, and its high genetic linkage to the disorder implicated a pathogenetical involvement of PLC-ß1 signaling system. The schizophrenia-related behavioral phenotypes displayed in the mutant mice lacking PLC-ß1 (PLC-ß1 KO) suggested that PLCß1-linked signaling pathways may be involved in the neural system whose function is disrupted in the pathogenesis of schizophrenia. In the brain, PLC-ß1 is known to be linked to muscarinic acetylcholine receptors, metabotropic glutamatergic, serotonergic, and oxytocinergic systems. The objective of this review is to provide an overview of the current knowledge regarding these schizophrenia-related behaviors and discuss the probable ways in which PLC-ß1signalling can be involved in the neural mechanisms for each behavior, which may help suggest future directions for research in this area.

Activity-dependent peptidergic modulation of the plateau-generating neuron B64 in the feeding network of Aplysia.

Many behaviors display various forms of activity-dependent plasticity. An example of such plasticity is the progressive shortening of the duration of protraction phase of feeding responses of Aplysia that occurs when feeding responses are repeatedly elicited. A similar protraction-duration shortening is observed in isolated ganglia of Aplysia when feeding-like motor programs are elicited through a prolonged stimulation of the command-like neuron CBI-2. Here, we investigate a cellular mechanism that may underlie this activity-dependent shortening of protraction duration of feeding motor programs. CBI-2 contains two neuropeptides, CP2 and FCAP. Previous work showed that CP2 shortens protraction duration of CBI-2 elicited programs. We show here that the same is true for FCAP. We also show that both CP2 and FCAP modulated the biophysical properties of a plateau-generating neuron, B64, that plays an important role in terminating the protraction phase of feeding motor programs. We find that prestimulation of CBI-2, as well as superfusion of CP2 and FCAP, lowered the threshold for activation of the plateau potential in B64. The threshold-lowering actions of CBI-2 prestimulation were occluded by superfusion of FCAP and CP2. Furthermore, at elevated temperature, conditions under which peptide release is prevented in Aplysia, prestimulation of CBI-2 does not lower the plateau-potential threshold, whereas superfusion of CP2 and FCAP does. Our findings are consistent with the hypothesis that peptides released from CBI-2 lower the threshold for activation of plateau potential in B64, thereby contributing to the shortening of protraction duration when CBI-2 is repeatedly activated.

Peptidergic contribution to posttetanic potentiation at a central synapse of aplysia.

Posttetanic potentiation (PTP)-like phenomena appear to be mediated by a variety of mechanisms. Although neuropeptides are located in a large number of neurons and many neuropeptides, like PTP, can enhance synaptic transmission, there is a paucity of studies indicating that peptides may actually participate in PTP. Here, we utilize a single central synapse in the feeding circuit of Aplysia to investigate a possible peptidergic contribution to PTP in the CNS. The cholinergic command-like interneuron, cerebral-buccal interneuron 2 (CBI-2), contains two neuropeptides, feeding circuit activating peptide (FCAP) and cerebral peptide 2 (CP2). Previous studies showed that tetanic prestimulation or repeated stimulation of CBI-2, as well as perfusion of FCAP and CP2, increase the size of the cholinergic excitatory postsynaptic potentials (EPSPs) that CBI-2 evokes in the motoneurons B61/62 and shorten the latency to initiate B61/62 firing in response to CBI-2 stimulation. We used temperature-dependent suppression of peptide release and occlusion experiments to examine the possible contribution of FCAP and CP2 to PTP at the CBI-2 to B61/62 synapse. When peptide release was suppressed, perfusion of exogenous peptides increased the size of posttetanic EPSPs. In contrast, when peptide release was not suppressed, exogenous peptides did not enhance the size of posttetanic EPSPs, thus indicating occlusion. Temperature manipulation and occlusion experiments also indicated that peptides extend PTP duration. This peptide-dependent prolongation of PTP has functional consequences in that it extends the duration of time during which the latency to initiate B61/62 firing in response to CBI-2 stimulation is shortened.