Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical NfκB signaling pathway.

Sex differences in luteinizing hormone (LH) release patterns are controlled by the hypothalamus, established during the perinatal period and required for fertility. Female mammals exhibit a cyclic surge pattern of LH release, while males show a tonic release pattern. In rodents, the LH surge pattern is dictated by the anteroventral periventricular nucleus (AVPV), an estrogen receptor-rich structure that is larger and more cell-dense in females. Sex differences result from mitochondrial cell death triggered in perinatal males by estradiol derived from aromatization of testosterone. Herein we provide an historical perspective and an update describing evidence that molecules important for cell survival and cell death in the immune system also control these processes in the developing AVPV. We conclude with a new model proposing that development of the female AVPV requires constitutive activation of the Tnfα, Tnf receptor 2, NfκB and Bcl2 pathway that is blocked by induction of Tnf receptor-associated factor 2-inhibiting protein (Traip) in the male.

Striatal-enriched protein tyrosine phosphatase (STEP) knockout mice have enhanced hippocampal memory.

Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that opposes synaptic strengthening by the regulation of key synaptic signaling proteins. Previous studies suggest a possible role for STEP in learning and memory. To demonstrate the functional importance of STEP in learning and memory, we generated STEP knockout (KO) mice and examined the effect of deletion of STEP on behavioral performance, as well as the phosphorylation and expression of its substrates. Here we report that loss of STEP leads to significantly enhanced performance in hippocampal-dependent learning and memory tasks. In addition, STEP KO mice displayed greater dominance behavior, although they were normal in their motivation, motor coordination, visual acuity and social interactions. STEP KO mice displayed enhanced tyrosine phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2), the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR) and proline-rich tyrosine kinase (Pyk2), as well as an increased phosphorylation of ERK1/2 substrates. Concomitant with the increased phosphorylation of NR2B, synaptosomal expression of NR1/NR2B NMDARs was increased in STEP KO mice, as was the GluR1/GluR2 containing α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs), providing a potential molecular mechanism for the improved cognitive performance. The data support a role for STEP in the regulation of synaptic strengthening. The absence of STEP improves cognitive performance, and may do so by the regulation of downstream effectors necessary for synaptic transmission.

Memória de reconhecimento social em ratos / Social recognition memory in rats / Mémoire de reconnaissance sociale chez les rats / Memoria de reconocimiento social en ratones

O paradigma intruso-residente vem sendo intensamente empregado em estudos para avaliar a memória de reconhecimento social em roedores. Tipicamente, ratos adultos (residentes) são expostos a dois encontros de 5 minutos cada com um mesmo intruso juvenil ou com juvenis diferentes; o intervalo entre encontros é usualmente 30 minutos. A quantidade de comportamentos sociais do residente, no segundo encontro, em relação a um intruso familiar é substancialmente menor do que o observado no primeiro encontro, o que não ocorre quando o segundo encontro envolve um juvenil novo; esse resultado caracteriza memória de reconhecimento social. Neste estudo discutimos achados recentes sobre os tipos de comportamentos usualmente incluídos nas categorias social e não-social, a influência da fase temporal, a interferência de rotinas laboratoriais na memória de reconhecimento social, modalidades sensoriais usualmente empregadas por roedores no processamento de informações na memória social e alternativas adicionais para o estudo da socialidade em roedores(AU)

The intruder-resident paradigm has been extensively employed in studies of social recognition memory in rodents. Typically, adult rats (residents) are exposed to two 5-min encounters with the same juvenile intruder or with two different juveniles; the interval between the encounters is 30 min. The amount of social behaviors exhibited by the resident rats toward the same intruder juvenile in the second encounter is substantially smaller when compared to both that seen in the first encounter and that seen toward a different juvenile; these results characterize social recognition memory. In this study we discuss recent findings related to behaviors usually included as social and non-social, the influence of the temporal phase on social behavior, the interference of laboratory routines on social recognition memory, sensory modalities usually employed by rodents for processing relevant information in the social memory and additional alternatives to study sociability in these animals(AU)

Le paradigme intrus-résident a été employée dans les études de memoire de reconnaissance social chez les rongeurs. Les rats adultes, nommés résidents, sont exposés à deux rencontres de 5min chacun, avec un même intrus juvénile ou avec des différents. L'intervalle de temps parmi les rencontres est 30 min. Le montant des comportements sociaux du résident, à la deuxième rencontre, parrapport a un intrus familiaire est sensiblement inférieur à celui observé à la première rencontre, ce qui ne se produit pas lorsque la deuxième recontre implique un nouveau juvenil. Ce résultat caractérise la mémoire de reconnaissance social. Cette étude discute des récentes conclusions du comportement social et non social, l'influence de la phase temportelle, l'ingérence dês routines de laboratoire dans cette memoire, les modalités sensorielles habituellement utilisées par les rongeurs dans le traitement de l'information sociale dans la mémoire et des solutions alternatifs pour l'étude de la socialité chez eux(AU)

El paradigma intruso-residente se viene utilizando extensivamente en estudios de memoria de reconocimiento social en roedores. Típicamente, un ratón adulto (residente) se expone a dos encuentros de 5 minutos cada uno con el mismo intruso juvenil o con dos juveniles diferentes; el intervalo entre los encuentros es de 30 minutos. El número de comportamientos sociales en el segundo encuentro exhibido por el residente y direccionado hacia el mismo intruso es substancialmente menor comparado con el primer encuentro o con un intruso nuevo; este tipo de disminución comportamental caracteriza memoria de reconocimiento social. En este estudio discutimos nuevos resultados relacionados con los comportamientos sociales y no-sociales, influencia de la fase circadiana, interferencia de las rutinas de laboratorio en la memoria de reconocimiento social, modalidades sensoriales empleadas por roedores para procesar información relevante a la memoria social y las alternativas adicionales para estudiar sociabilidad en estos animales(AU)

Memória de reconhecimento social em ratos / Social recognition memory in rats / Mémoire de reconnaissance sociale chez les rats / Memoria de reconocimiento social en ratones

O paradigma intruso-residente vem sendo intensamente empregado em estudos para avaliar a memória de reconhecimento social em roedores. Tipicamente, ratos adultos (residentes) são expostos a dois encontros de 5 minutos cada com um mesmo intruso juvenil ou com juvenis diferentes; o intervalo entre encontros é usualmente 30 minutos. A quantidade de comportamentos sociais do residente, no segundo encontro, em relação a um intruso familiar é substancialmente menor do que o observado no primeiro encontro, o que não ocorre quando o segundo encontro envolve um juvenil novo; esse resultado caracteriza memória de reconhecimento social. Neste estudo discutimos achados recentes sobre os tipos de comportamentos usualmente incluídos nas categorias social e não-social, a influência da fase temporal, a interferência de rotinas laboratoriais na memória de reconhecimento social, modalidades sensoriais usualmente empregadas por roedores no processamento de informações na memória social e alternativas adicionais para o estudo da socialidade em roedores

The intruder-resident paradigm has been extensively employed in studies of social recognition memory in rodents. Typically, adult rats (residents) are exposed to two 5-min encounters with the same juvenile intruder or with two different juveniles; the interval between the encounters is 30 min. The amount of social behaviors exhibited by the resident rats toward the same intruder juvenile in the second encounter is substantially smaller when compared to both that seen in the first encounter and that seen toward a different juvenile; these results characterize social recognition memory. In this study we discuss recent findings related to behaviors usually included as social and non-social, the influence of the temporal phase on social behavior, the interference of laboratory routines on social recognition memory, sensory modalities usually employed by rodents for processing relevant information in the social memory and additional alternatives to study sociability in these animals

Le paradigme intrus-résident a été employée dans les études de memoire de reconnaissance social chez les rongeurs. Les rats adultes, nommés résidents, sont exposés à deux rencontres de 5min chacun, avec un même intrus juvénile ou avec des différents. L'intervalle de temps parmi les rencontres est 30 min. Le montant des comportements sociaux du résident, à la deuxième rencontre, parrapport a un intrus familiaire est sensiblement inférieur à celui observé à la première rencontre, ce qui ne se produit pas lorsque la deuxième recontre implique un nouveau juvenil. Ce résultat caractérise la mémoire de reconnaissance social. Cette étude discute des récentes conclusions du comportement social et non social, l'influence de la phase temportelle, l'ingérence dês routines de laboratoire dans cette memoire, les modalités sensorielles habituellement utilisées par les rongeurs dans le traitement de l'information sociale dans la mémoire et des solutions alternatifs pour l'étude de la socialité chez eux

El paradigma intruso-residente se viene utilizando extensivamente en estudios de memoria de reconocimiento social en roedores. Típicamente, un ratón adulto (residente) se expone a dos encuentros de 5 minutos cada uno con el mismo intruso juvenil o con dos juveniles diferentes; el intervalo entre los encuentros es de 30 minutos. El número de comportamientos sociales en el segundo encuentro exhibido por el residente y direccionado hacia el mismo intruso es substancialmente menor comparado con el primer encuentro o con un intruso nuevo; este tipo de disminución comportamental caracteriza memoria de reconocimiento social. En este estudio discutimos nuevos resultados relacionados con los comportamientos sociales y no-sociales, influencia de la fase circadiana, interferencia de las rutinas de laboratorio en la memoria de reconocimiento social, modalidades sensoriales empleadas por roedores para procesar información relevante a la memoria social y las alternativas adicionales para estudiar sociabilidad en estos animales

Estradiol acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy.

Estradiol (E2) is a potent neuroactive steroid that acts through both nuclear and membrane estrogen receptors (ER) found widely distributed in the brain. Although long known for its role in the neural control of reproduction, more recent work demonstrates that E2 also affects learning and memory, as well as anxiety and depressive symptoms. These findings prompted studies on the neural consequences of long-term E2 deprivation in postmenopausal women. Despite hundreds of studies in animal models and women, the advisability of hormone replacement therapy (HRT) for neuroprotection remains a contentious issue because the effects of estrogen vary among studies. One difficulty in reconciling the conflicting results is the lack of integration across the neuroscience sub-disciplines that contribute to the field. To address this issue, we first review data on E2 regulation of cognition and mood, as well as on factors that may contribute to the disparate findings across studies. GABA and glutamate are proximal regulators of cognition and mood; therefore we next review review data showing that E2 acts through nuclear- and membrane-initiated mechanisms to regulate GABA and glutamate signaling, respectively. We also review evidence that these E2 signaling mechanisms change with age. Finally, we propose a molecular and cellular model of how E2 can have positive, negative, or no effects on neural functions in the aging brain, and we highlight the current gaps in the literature. Addressing these gaps will facilitate development of the mechanism-based strategies needed for designing more effective HRT regimens.

A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum.

BACKGROUND: Chronic, intermittent exposure to psychostimulant drugs results in striatal neuroadaptations leading to an increase in an array of behavioral responses on subsequent challenge days. A brain-specific striatal-enriched tyrosine phosphatase (STEP) regulates synaptic strengthening by dephosphorylating and inactivating several key synaptic proteins. This study tests the hypothesis that a substrate-trapping form of STEP will prevent the development of amphetamine-induced stereotypies. METHODS: A substrate-trapping STEP protein, TAT-STEP (C-S), was infused into the ventrolateral striatum on each of 5 consecutive exposure days and 1 hour before amphetamine injection. Animals were challenged to see whether sensitization to the stereotypy-producing effects of amphetamine developed. The same TAT-STEP (C-S) protein was used on acute striatal slices to determine the impact on long-term potentiation and depression. RESULTS: Infusion of TAT-STEP (C-S) blocks the increase of amphetamine-induced stereotypies when given during the 5-day period of sensitization. The TAT-STEP (C-S) has no effect if only infused on the challenge day. Treatment of acute striatal slices with TAT-STEP (C-S) blocks the induction of long-term potentiation and potentates long-term depression. CONCLUSIONS: A substrate trapping form of STEP blocks the induction of amphetamine-induced neuroplasticity within the ventrolateral striatum and supports the hypothesis that STEP functions as a tonic break on synaptic strengthening.

Circadian phase and intertrial interval interfere with social recognition memory.

A modified version of the social habituation/dis-habituation paradigm was employed to examine social recognition memory in Wistar rats during two opposing (active and inactive) circadian phases, using different intertrial intervals (30 and 60 min). Wheel-running activity was monitored continuously to identify circadian phase. To avoid possible masking effects of the light-dark cycle, the rats were synchronized to a skeleton photoperiod, which allowed testing during different circadian phases under identical lighting conditions. In each trial, an infantile intruder was introduced into an adult's home-cage for a 5-minute interaction session, and social behaviors were registered. Rats were exposed to 5 trials per day for 4 consecutive days: on days 1 and 2, each resident was exposed to the same intruder; on days 3 and 4, each resident was exposed to a different intruder in each trial. The resident's social investigatory behavior was more intense when different intruders were presented compared to repeated presentation of the same intruder, suggesting social recognition memory. This effect was stronger when the rats were tested during the inactive phase and when the intertrial interval was 60 min. These findings suggest that social recognition memory, as evaluated in this modified habituation/dis-habituation paradigm, is influenced by the circadian rhythm phase during which testing is performed, and by intertrial interval.

Temporal lobe epilepsy and social behavior: an animal model for autism?

Social behavior depends on the integrity of social brain circuitry. The temporal lobe is an important part of the social brain, and manifests morphological and functional alterations in autism spectrum disorders (ASD). Rats with temporal lobe epilepsy (TLE), induced with pilocarpine, were subjected to a social discrimination test that has been used to investigate potential animal models of ASD, and the results were compared with those for the control group. Rats with TLE exhibited fewer social behaviors than controls. No differences were observed in nonsocial behavior between groups. The results suggest an important role for the temporal lobe in regulating social behaviors. This animal model might be used to explore some questions about ASD pathophysiology.