Rats answer an unexpected question after incidental encoding

A fundamental aspect of episodic memory is that retrieval of information can occur when encoding is incidental and memory assessment is unexpected. These features are difficult to model in animals because behavioral training likely gives rise to well-learned expectations about the sequence of events. Thus, the possibility remains that animals may solve an episodic memory test by using well-learned semantic rules without remembering the episode at memory assessment. Here we show that rats can answer an unexpected question after incidental encoding in a hippocampal-dependent manner, consistent with the use of episodic memory. Rats were initially trained to report about a recent event (food versus no food) and separately searched for food where there was no expectation of being asked about the presence of food. To test episodic memory, we gave rats the opportunity to incidentally encode the presence or absence of food and unexpectedly asked them to report about the recent event. Temporary inactivation of the CA3 region of the hippocampus with bilateral infusions of lidocaine selectively eliminated the ability of rats to answer the unexpected, but not the expected, question. Our studies suggest that rats remember an earlier episode after incidental encoding based upon hippocampal-dependent episodic memory.     

Resistance to experimental autoimmune encephalomyelitis and impaired IL-17 production in protein kinase C theta-deficient mice

The protein kinase C theta (PKC theta) serine/threonine kinase has been implicated in signaling of T cell activation, proliferation, and cytokine production. However, the in vivo consequences of ablation of PKC theta on T cell function in inflammatory autoimmune disease have not been thoroughly examined. In this study we used PKC theta-deficient mice to investigate the potential involvement of PKC theta in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the CNS. We found that PKC theta-/- mice immunized with the myelin oligodendrocyte glycoprotein (MOG) peptide MOG(35-55) were completely resistant to the development of clinical experimental autoimmune encephalomyelitis compared with wild-type control mice. Flow cytometric and histopathological analysis of the CNS revealed profound reduction of both T cell and macrophage infiltration and demyelination. Ex vivo MOG(35-55) stimulation of splenic T lymphocytes from immunized PKC theta-/- mice revealed significantly reduced production of the Th1 cytokine IFN-gamma as well as the T cell effector cytokine IL-17 despite comparable levels of IL-2 and IL-4 and similar cell proliferative responses. Furthermore, IL-17 expression was dramatically reduced in the CNS of PKC theta-/- mice compared with wild-type mice during the disease course. In addition, PKC theta-/- T cells failed to up-regulate LFA-1 expression in response to TCR activation, and LFA-1 expression was also significantly reduced in the spleens of MOG(35-55)-immunized PKC theta-/- mice as well as in in vitro-stimulated CD4+ T cells compared with wild-type mice. These results underscore the importance of PKC theta in the regulation of multiple T cell functions necessary for the development of autoimmune disease.     

TNF is important for pathogen control and limits brain damage in murine cerebral listeriosis

Cerebral listeriosis is a life-threatening disease. However, little is known about the bacterial virulence factors responsible for the severe course of disease and the factors of the immune system contributing to the control of Listeria monocytogenes (LM) or even to the damage of the brain. To analyze the importance of the actA gene of LM, which mediates cell-to-cell spread of intracellular LM, the function of TNF in murine cerebral listeriosis was studied. C57BL/6 mice survived an intracerebral (i.c.) infection with actA-deficient LM, but succumbed to infection with wild-type (WT) LM. Upon infection with actA-deficient LM, macrophages and microglial cells rapidly, and later LM-specific CD4 and CD8 T cells, produced TNF. In contrast to WT mice, TNF-deficient animals succumbed to the infection within 4 days due to failure of control of LM. Histology identified a more severe meningoencephalitis, brain edema, and neuronal damage, but a reduced inducible NO synthase expression in TNF-deficient mice. Reciprocal bone marrow chimeras between WT and TNF-deficient mice revealed that hematogenously derived TNF was essential for survival, whereas TNF produced by brain-resident cells was less important. Death of TNF-deficient mice could be prevented by LM-specific T cells induced by an active immunization before i.c. infection. However, brain pathology and inflammation of immunized TNF-deficient mice were still more severe. In conclusion, these findings identify a crucial role of TNF for the i.c. control of LM and survival of cerebral listeriosis, whereas TNF was not responsible for the destruction of brain tissue.     

Pyridine-2-propanoic acids: Discovery of dual PPARalpha/gamma agonists as antidiabetic agents

A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling.     

Episodic-like memory in the rat

A fundamental question in comparative cognition is whether animals remember unique, personal past experiences. It has long been argued that memories for specific events (referred to as episodic memory) are unique to humans. Recently, considerable evidence has accumulated to show that food-storing birds possess critical behavioral elements of episodic memory, referred to as episodic-like memory in acknowledgment of the fact that behavioral criteria do not assess subjective experiences. Here we show that rats have a detailed representation of remembered events and meet behavioral criteria for episodic-like memory. We provided rats with access to locations baited with distinctive (e.g., grape and raspberry) or nondistinctive (regular chow) flavors. Locations with a distinctive flavor replenished after a long but not a short delay, and locations with the nondistinctive flavor never replenished. One distinctive flavor was devalued after encoding its location by prefeeding that flavor (satiation) or by pairing it with lithium chloride (acquired taste aversion), while the other distinctive flavor was not devalued. The rats selectively decreased revisits to the devalued distinctive flavor but not to the nondevalued distinctive flavor. The present studies demonstrate that rats selectively encode the content of episodic-like memories.     

CMIP and ATP2C2 Modulate Phonological Short-Term Memory in Language Impairment

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 × 10⁻⁷ at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 × 10⁻⁵ at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.