Histone acetylation is a chromatin modification critically involved in gene regulation during many neural processes. The enzymes that regulate levels of histone acetylation are histone acetyltransferases (HATs), which activate gene expression and histone deacetylases (HDACs), that repress gene expression. Acetylation together with other histone and DNA modifications regulate transcription profiles for specific cellular functions. Our previous research has demonstrated a pivotal role for cyclicAMP response element binding protein (CREB)-binding protein (CBP), a histone acetyltransferase, in long-term memory for novel object recognition (NOR). In fact, every genetically modifiedCbp mutant mouse characterized thus far exhibits impaired long-term memory for NOR. These results suggest that long-term memory for NOR is especially sensitive to alterations in CBP activity. Thus, in the current study, we examined the role of HDACs in memory for NOR. We found that inducing a histone hyperacetylated state via HDAC inhibition transforms a learning event that would not normally result in long-term memory into an event that is now remembered long-term. We have also found that HDAC inhibition generates a type of long-term memory that persists beyond a point at which normal memory for NOR fails. This result is particularly interesting because one alluring aspect of examining the role of chromatin modifications in modulating transcription required for long-term memory processes is that these modifications may provide potentially stable epigenetic markers in the service of activating and/or maintaining transcriptional processes.CBP ͉ chromatin ͉ epigenetic ͉ acetylation ͉ CREB

Transcription of genes required for long-term memory not only involves transcription factors, but also enzymatic protein complexes that modify chromatin structure. Chromatin-modifying enzymes, such as the histone acetyltransferase (HAT) CREB (cyclic-AMP response element binding) binding protein (CBP), are pivotal for the transcriptional regulation required for long-term memory. Several studies have shown that CBP and histone acetylation are necessary for hippocampusdependent long-term memory and hippocampal long-term potentiation (LTP). Importantly, every genetically modified Cbp mutant mouse exhibits long-term memory impairments in object recognition. However, the role of the hippocampus in object recognition is controversial. To better understand how chromatin-modifying enzymes modulate long-term memory for object recognition, we first examined the role of the hippocampus in retrieval of long-term memory for object recognition or object location. Muscimol inactivation of the dorsal hippocampus prior to retrieval had no effect on long-term memory for object recognition, but completely blocked long-term memory for object location. This was consistent with experiments showing that muscimol inactivation of the hippocampus had no effect on long-term memory for the object itself, supporting the idea that the hippocampus encodes spatial information about an object (such as location or context), whereas cortical areas (such as the perirhinal or insular cortex) encode information about the object itself. Using location-dependent object recognition tasks that engage the hippocampus, we demonstrate that CBP is essential for the modulation of long-term memory via HDAC inhibition. Together, these results indicate that HDAC inhibition modulates memory in the hippocampus via CBP and that different brain regions utilize different chromatin-modifying enzymes to regulate learning and memory.

Glucocorticoid hormones enhance the consolidation of long-term memory of emotionally arousing training experiences. This memory enhancement requires activation of the cAMP-dependent kinase pathway and the subsequent phosphorylation of cAMP responseelement binding (CREB) protein. Here, we demonstrate that glucocorticoids enhance the consolidation of hippocampus-dependent and hippocampus-independent aspects of object recognition memory via chromatin modification. More specifically, systemic corticosterone increases histone acetylation, a form of chromatin modification, in both the hippocampus and insular cortex following training on an object recognition task. This led us to examine whether increasing histone acetylation via histone deacetylase (HDAC) inhibition enhances memory in a manner similar to corticosterone. We found a double dissociation between posttraining HDAC inhibitor infusion into the insular cortex and hippocampus on the enhancement of object recognition and object location memory, respectively. In determining the molecular pathway upstream of glucocorticoids' effects on chromatin modification, we found that activation of membraneassociated glucocorticoid receptors (GRs) and the subsequent interaction between phospho-CREB and CREB-binding protein (CBP) appear to be necessary for glucocorticoids to enhance memory consolidation via chromatin modification. In contrast, mineralocorticoid receptors (MRs) do not appear to be involved. The findings also indicate that glucocorticoid activity has differential influences on hippocampus-dependent and hippocampus-independent components of memory for objects.

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Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington's disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG140 expansion repeat (CAG140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG140 KI and WT mice, such that CAG140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar-thalamic and somatosensory regions. Significant hypoperfusion was also noted in CAG140 KI mice in the prelimbic and cingulate cortex (medial prefrontal area) and the hippocampus - areas associated with cognitive processing and mood. Changes in rCBF were apparent in the absence of motor deficits (rotarod test) or atrophy in the striatum (caudate-putamen) or hemispheric volume. Our results suggest a functional reorganization of whole-brain networks at a presymptomatic stage in the life of the CAG140 KI mouse. Functional brain mapping in animals may, in the future, serve as a translational biomarker for identifying sites of early synaptic change in the HD brain and for directing targeted preclinical molecular studies and clinical therapies.

Morcellation of benign uterine tumors allows for removal of the tumors via minimally invasive laparoscopic procedures. However, in rare cases, morcellation has been associated with upstaging of unexpected malignancies. Morcellation has also been associated with dissemination of benign pathologic processes such as endometriosis and leiomyomas. Endometrial stromal sarcoma typically arises in the uterine cavity, although cases of extrauterine endometrioid stromal sarcoma arising out of foci of endometriosis have been reported. Dissemination of endometrial stromal sarcomas can be an unintended consequence of morcellation procedures, as can dissemination of endometriosis, from which endometrioid stromal sarcomas can arise. Herein, we report a case of a 55-year-old woman who was found to have disseminated endometriosis and low-grade endometrioid stromal sarcoma, with bowel and liver parenchymal metastasis, 7 years after undergoing supracervical hysterectomy with unconfined uterine morcellation for adenomyosis. Our case highlights the potential for malignant transformation of disseminated adenomyosis/endometriosis and the importance of patient counseling and shared decision-making prior to morcellation procedures.

No abstract

Mesothelial cell inclusions in cervical lymph nodes are of exceedingly rare occurrence and can be mistaken for metastatic adenocarcinoma. We report the case of a 27-year-old woman with a history of chronic myelogenous leukemia, diagnosed at age 5 years, and a recent diagnosis of alveolar soft part sarcoma of the left parotid gland. The patient underwent a left parotidectomy and neck dissection with intraoperative finding of abnormal lymph nodes in levels II to V. Histological examination revealed clusters of bland cells with pseudoglandular formation in 6 of 14 level IV/V lymph nodes. Immunological stains were consistent with mesothelial origin, and the diagnosis of benign mesothelial cell inclusions was made. Recognition of this entity in the evaluation of lymph nodes is important to prevent misdiagnosis of metastatic disease, particularly in a patient with multiple known malignancies.