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Social cognition enables individuals to understand others' intentions. Social memory is a necessary component of this process, for without it, subsequent encounters are devoid of any historical information. The CA2 area of the hippocampus, particularly the vasopressin 1b receptor (Avpr1b) expressed there, is necessary for memory formation. We used optogenetics to excite vasopressin terminals, originating from the hypothalamic paraventricular nucleus, in the CA2 of mice. This markedly enhanced their social memory if the stimulation occurred during memory acquisition, but not retrieval. This effect was blocked by an Avpr1b antagonist. Finally, this enhanced memory is resistant to the social distraction of an introduced second mouse, important for socially navigating populations of individuals. Our results indicate the CA2 can increase the salience of social signals. Targeted pharmacotherapy with Avpr1b agonists or deep brain stimulation of the CA2 are potential avenues of treatment for those with declining social memory as in various dementias.

The vasopressin 1b receptor (Avpr1b) is critical for social memory and social aggression in rodents, yet little is known about its specific roles in these behaviors. Some clues to Avpr1b function can be gained from its profile of expression in the brain, which is largely limited to the pyramidal neurons of the CA2 region of the hippocampus, and from experiments showing that inactivation of the gene or antagonism of the receptor leads to a reduction in social aggression. Here we show that partial replacement of the Avpr1b through lentiviral delivery into the dorsal CA2 region restored the probability of socially motivated attack behavior in total Avpr1b knockout mice, without altering anxiety-like behaviors. To further explore the role of the Avpr1b in this hippocampal region, we examined the effects of Avpr1b agonists on pyramidal neurons in mouse and rat hippocampal slices. We found that selective Avpr1b agonists induced significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b knockout mice. In a way that is mechanistically very similar to synaptic potentiation induced by oxytocin, Avpr1b agonist-induced potentiation of CA2 synapses relies on NMDA (N-methyl-D-aspartic acid) receptor activation, calcium and calcium/calmodulin-dependent protein kinase II activity, but not on cAMP-dependent protein kinase activity or presynaptic mechanisms. Our data indicate that the hippocampal CA2 is important for attacking in response to a male intruder and that the Avpr1b, likely through its role in regulating CA2 synaptic plasticity, is a necessary mediator.

Increased aggression is commonly associated with many neurological and psychiatric disorders. Current treatments are largely empirical and are often accompanied by severe side effects, underscoring the need for a better understanding of the neural bases of aggression. Vasopressin, acting through its 1a receptor subtype, is known to affect aggressive behaviors. The vasopressin 1b receptor (V1bR) is also expressed in the brain, but has received much less attention due to a lack of specific drugs. Here we report that mice without the V1bR exhibit markedly reduced aggression and modestly impaired social recognition. By contrast, they perform normally in all the other behaviors that we have examined, such as sexual behavior, suggesting that reduced aggression and social memory are not simply the result of a global deficit in sensorimotor function or motivation. Fos-mapping within chemosensory responsive regions suggests that the behavioral deficits in V1bR knockout mice are not due to defects in detection and transmission of chemosensory signals to the brain. We suggest that V1bR antagonists could prove useful for treating aggressive behavior seen, for example, in dementias and traumatic brain injuries.

It has been previously suggested that oxytocin (Oxt) may act as a natural antipsychotic. To test this hypothesis, we investigated whether disruption of the oxytocin gene (Oxt−/−) made mice more susceptible to the psychosis-related effects of amphetamine (Amp), apomorphine (Apo) and phencyclidine (PCP). We examined drug-induced changes in the prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating deficits characteristic of several psychiatric and neurological disorders, including schizophrenia. We found that treatment with Amp, Apo and PCP all had effects on PPI. However, in Oxt−/− mice, but not Oxt+/+ mice, PCP treatment resulted in large PPI deficits. As PCP is a noncompetitive N -methyl- D -aspartic acid receptor antagonist, these findings suggest that the absence of Oxt alters the glutamatergic component of the PPI.

Arg8]vasopressin (AVP) stimulates adrenocorticotropic hormone release from the anterior pituitary by acting on the V1b AVP receptor. This receptor can be distinguished from the vascular/hepatic V1a and renal V2 AVP receptors by its differential binding affinities for structural analogous of AVP. Recent studies have shown that the cloned V1a and V2 receptors are structurally related. We have isolated a clone encoding the V1b receptor from a rat pituitary cDNA library using polymerase chain reaction (PCR)-based methodology. The rat V1b receptor is a protein of 421 amino acids that has 37-50% identity with the V1a and V2 receptors. Homology is particularly high in the seven putative membrane-spanning domains of these guanine nucleotide-binding protein-coupled receptors. Expression of the recombinant receptor in mammalian cells shows the same binding specificity for AVP agonists and antagonists as the rat pituitary V1b receptor. AVP-stimulated phosphotidylinositol hydrolysis and intracellular Ca2+mobilization in Chinese hamster ovary or COS-7 cells expressing the cloned receptor suggest second messenger signaling through phospholipase C. RNA blot analysis, reverse transcription PCR, and in situ hybridization studies reveal that V1b receptor mRNA is expressed in the majority of pituitary corticotropes as well as in multiple brain regions and a number of peripheral tissues, including kidney, thymus, heart, lung, spleen, uterus, and breast. Thus, the V1b receptor must mediate some of the diverse biological effects of AVP in the pituitary as well as other organs.

IntroductionKinematic alignment (KA) in total knee arthroplasty (TKA) matches component position to the pre-arthritic anatomy of an individual patient, with the aim of improving functional outcomes. Recent randomised controlled trials (RCTs) comparing KA to traditional neutral mechanical alignment (MA) have been mixed. This collaborative study combined raw data from RCTs, aiming to compare functional outcomes between KA using patient-specific instrumentation (PSI) and MA, and whether any patient subgroups may benefit more from KA technique.Materials and methodsA literature search in PubMed, EMBASE and Cochrane databases identified four randomised controlled trials comparing patients undergoing TKA using PSI-KA and MA. Unpublished data including Western Ontario McMaster Universities Arthritis Index (WOMAC) and Knee Society Score (KSS) were obtained from study authors. Meta-analysis compared MA to KA change (post-op minus pre-op) scores. Subgroup-analysis on KA patients looked for subgroups more likely to benefit from KA and the impact of PSI accuracy.ResultsMeta-analyses of change scores in 229 KA patients versus 229 MA patients were no different from WOMAC (mean difference 3.4; 95% confidence interval − 0.5 to 7.3), KSS function (1.3, − 3.9 to 6.4) or KSS combined (7.2, − 0.8 to 15.2). A small advantage was seen for KSS pain in the KA group (3.6, 95% CI 0.2–7.1). Subgroup-analysis showed no difference between varus, valgus and neutral pre-operative alignment groups, and those who did and did not achieve KA plans. Pain-free patients at 1-year were more likely to achieve KA plans.ConclusionPatient-reported outcome scores following TKA using PSI-KA are similar to MA. No identifiable subgroups benefited more from KA, and long-term results remain unknown. Inaccuracy of the PSI system used in KA patients could potentially affect outcome.

Purpose Case reports and anecdotal experiences suggest that some men develop parkinsonism after initiating androgen deprivation therapy (ADT) for the treatment of prostate cancer, possibly due to neurophysiological effects of changes in testosterone and/or estrogen. We hypothesized that ADT would increase the risk of parkinsonism. Methods Using linked administrative databases in Ontario, Canada, men age 40 or older with prostate cancer on continuous ADT for at least 6 months or who underwent bilateral orchiectomy ( n  = 38,931) were matched 1:1 with men with prostate cancer who had never received ADT. Treated and untreated groups were range-matched on age at index date and year of diagnosis, and propensity-matched on comorbidities, medications, cardiovascular risk factors, and socio-economic variables. A competing risk analysis was conducted where the primary outcome was time to a new diagnosis of parkinsonism. Results The cohort was followed for a mean of 5.76 years. Based on the results from the multivariable cause-specific hazard regression model, the adjusted relative rate of experiencing parkinsonism among ADT users compared to non-users was 0.74 (95% confidence interval (CI) 0.67–0.83, p  < 0.0001). The adjusted relative rate of experiencing the competing event of death among ADT users compared to non-users was 1.33 (95% CI 1.30–1.36, p  < 0.0001). The 5-year incidence of parkinsonism was 1.03% in ADT users versus 1.56% in non-users. Conclusion Contrary to our hypothesis, continuous ADT use for at least 6 months in men with prostate cancer was not associated with an increased risk of parkinsonism after accounting for the substantial competing risk of death.

Clinicians have long recognized that congenital deficiency of iodine (a component of thyroid hormone) somehow damages the human embryonic nervous system, causing sensori-neural deafness. Recently, a deletion encompassing most of the human β thyroid hormone receptor (TRβ) gene has been found in children who are neurologically normal except for one striking defect: profound sensori-neural deafness. We now show that the TRβ gene is prominently expressed very early in rat inner ear development. This expression is remarkable because both TRβ1 and TRβ2 mRNAs are restricted, as early as embryonic day 12.5, to that portion of the embryonic inner ear that gives rise to the cochlea, the structure responsible for converting sound into neural impulses. The timing of this expression, when correlated with human inner ear development, raises the possibility that TRs may act in human ontogenesis earlier than previously suspected. These results provide a rare correlation between a specific human neurologic deficit (deafness) and transcription factor expression in a highly discrete embryonic cell population (ventral otocyst). TRα gene expression is also prominent in the developing cochlea, but, in contrast to the restricted pattern of TRβ gene expression, TRα1 and TRα2 transcripts are also found in inner ear structures responsible for balance. Deafness in children homozygous for a large deletion in the TRβ gene suggests that cochlear α1 TRs cannot functionally compensate for the absence of TRβ1 and TRβ2. The developing inner ear may, therefore, represent an example of TR isoform-specific transcriptional regulation in vivo.

We have recently found that susceptibility to streptococcal cell wall (SCW)-induced arthritis in Lewis (LEW/N) rats is due, in part, to defective inflammatory and stress mediator-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Conversely, the relative arthritis resistance of histocompatible Fischer (F344/N) rats is related to their intact responses to the same stimuli. Specifically, LEW/N rats, in contrast to F344/N rats, have markedly impaired plasma corticotropin and corticosterone responses to SCW, recombinant human interleukin 1α , the serotonin agonist quipazine, or synthetic rat/human corticotropin-releasing hormone (CRH). To explore the mechanism of this defect, we examined the functional integrity of the hypothalamic CRH neuron in LEW/N rats compared to F344/N rats. LEW/N rats, in contrast to F344/N rats, showed profoundly deficient paraventricular nucleus CRH mRNA levels and hypothalamic CRH content in response to SCW. Compared to F344/N rats, there was no increase in LEW/N hypothalamic CRH content or CRH release from explanted LEW/N hypothalami in organ culture in response to recombinant interleukin 1α . These data provide strong evidence that the defective LEW/N corticotropin and corticosterone responses to inflammatory and other stress mediators, and the LEW/N susceptibility to experimental arthritis, are due in part to a hypothalamic defect in the synthesis and secretion of CRH. The additional finding of deficient expression in LEW/N rats of the hypothalamic enkephalin gene, which is coordinately regulated with the CRH gene in response to stress, suggests that the primary defect is not in the CRH gene but is instead related to its inappropriate regulation.

We used in situ hybridization histochemistry with synthetic oligodeoxyribonucleotide probes to identify cells that synthesize mRNAs encoding tyrosine hydroxylase in the mesencephalon and substance P, enkephalin, and dynorphin in the rat forebrain. Dopaminergic cells in the mesencephalon project to the forebrain and influence neuropeptide levels. We examined the effect of unilateral 6-hydroxydopamine lesions (which eliminated tyrosine hydroxylase mRNA-containing cells in the mesencephalon) on substance P, enkephalin, and dynorphin mRNA levels. Substance P mRNA levels were depressed, whereas enkephalin mRNA levels were elevated in consecutive sections from striatal areas in all animals. The effects of the lesions on dynorphin mRNA levels were less robust, and considerable variation between animals was observed. Changes were evident in the levels of message in individual cells but not in the numbers of labeled cells. These effects were not uniform throughout the dopamine-innervated areas, suggesting degrees of control not apparent with RNA blot-hybridization or dotblot analyses.