Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation.

Toll-like receptors (TLRs) play a crucial role in early innate immune responses to inflammatory agents and pathogens. In the brain, some members of the TLR family are expressed in glial cells and neurons. In particular, TLR4 has been involved in learning and memory processes, stress-induced adaptations, and pathogenesis of neurodegenerative disorders. However, the role of TLR4 in emotional behaviors and their underlying mechanisms are poorly understood. In this study, we investigated the role of TLR4 in emotional and social behavior by using different behavioral approaches, and assessed potential molecular alterations in important brain areas involved in emotional responses. TLR4 knockout (KO) mice displayed increased anxiety-like behavior and reduced social interaction compared to wild type control mice. This behavioral phenotype was associated with an altered expression of genes known to be involved in emotional behavior [e.g., brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptors (mGluRs)]. Interestingly, the mRNA expression of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) was strongly upregulated in emotion-related regions of the brain in TLR4 KO mice. In addition, the phosphorylation levels at Thr75 and Ser97 in DARPP-32 were increased in the frontal cortex of TLR4 KO male mice. These findings indicate that TLR4 signaling is involved in emotional regulation through modulation of DARPP-32, which is a signaling hub that plays a critical role in the integration of numerous neurotransmitter systems, including dopamine and glutamate.

The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior.

Recent studies have revealed that the gut microbiota modulates brain development and behavior, but the underlying mechanisms are still poorly understood. Here, we show that bacterial peptidoglycan (PGN) derived from the commensal gut microbiota can be translocated into the brain and sensed by specific pattern-recognition receptors (PRRs) of the innate immune system. Using expression-profiling techniques, we demonstrate that two families of PRRs that specifically detect PGN (that is, PGN-recognition proteins and NOD-like receptors), and the PGN transporter PepT1 are highly expressed in the developing brain during specific windows of postnatal development in both males and females. Moreover, we show that the expression of several PGN-sensing molecules and PepT1 in the developing striatum is sensitive to manipulations of the gut microbiota (that is, germ-free conditions and antibiotic treatment). Finally, we used the PGN-recognition protein 2 (Pglyrp2) knockout mice to examine the potential influence of PGN-sensing molecules on brain development and behavior. We demonstrate that the absence of Pglyrp2 leads to alterations in the expression of the autism risk gene c-Met, and sex-dependent changes in social behavior, similar to mice with manipulated microbiota. These findings suggest that the central activation of PRRs by microbial products could be one of the signaling pathways mediating the communication between the gut microbiota and the developing brain.

Métodos de evaluación de trastornos cognitivos en modelos animales / Methods to evaluate cognitive disorders in animal models

Introducción. El aumento de la prevalencia de la disfunción cognitiva y la demencia, asociado, entre otros factores, al envejecimiento de la población en los países desarrollados, ha despertado un gran interés por el estudio de la etiopatogénesis del déficit cognitivo y de las posibles dianas farmacológicas para mejorar la función intelectual o frenar la neurodegeneraciónsubyacente en estos síntomas. Desarrollo y conclusiones. Un instrumento esencial a tal fin es la utilización de modelos animales de las enfermedades humanas que cursan clínicamente con deterioro cognitivo y demencia. En esta revisión analizamos los modelos animales de estos trastornos y las principales pruebas que, mediante la observación de la evolución de la conducta del animal de experimen-tación, permiten valorar sus funciones cognitivas y su modificación por los tratamientos experimentales que se quieran ensayar, de cara a su posible aplicación a los pacientes

Introduction. The increasing prevalence of cognitive dysfunction and dementia associated, among others, topopulation aging in developed countries has grown a great interest in the study of the etiopathogenesis of cognitive deficit and the likely pharmacological targets which improve intellectual function or alter the neurodegeneration underlying these symptoms. Development and conclusions. An essential tool for that purpose is the use of animal models of human-relatedpathologies which clinically develop with cognitive impairment and dementia. In this review we will analyse the animal models of these disorders and, specially, the main tests that, by means of the observational evolution of the experimental animal, allow assessing its cognitive functions and its modification by experimental treatments that are wanted to investigate for its eventual introduction into clinics

[Methods to evaluate cognitive disorders in animal models]. / Métodos de evaluación de trastornos cognitivos en modelos animales.

INTRODUCTION: The increasing prevalence of cognitive dysfunction and dementia associated, among others, to population aging in developed countries has grown a great interest in the study of the etiopathogenesis of cognitive deficit and the likely pharmacological targets which improve intellectual function or alter the neurodegeneration underlying these symptoms. DEVELOPMENT AND CONCLUSIONS: An essential tool for that purpose is the use of animal models of human-related pathologies which clinically develop with cognitive impairment and dementia. In this review we will analyse the animal models of these disorders and, specially, the main tests that, by means of the observational evolution of the experimental animal, allow assessing its cognitive functions and its modification by experimental treatments that are wanted to investigate for its eventual introduction into clinics.