- Relaxin-3 Inputs Target Hippocampal Interneurons and Deletion of Hilar Relaxin-3 Receptors in 'Floxed-RXFP3' Mice Impairs Spatial Memory. [Journal Article]
- HHippocampus 2017 Jan 18
- Hippocampus is innervated by γ-aminobutyric acid (GABA) 'projection' neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at ga...
Hippocampus is innervated by γ-aminobutyric acid (GABA) 'projection' neurons of the nucleus incertus (NI), including a population expressing the neuropeptide, relaxin-3 (RLN3). In studies aimed at gaining an understanding of the role of RLN3 signaling in hippocampus via its Gi/o -protein-coupled receptor, RXFP3, we examined the distribution of RLN3-immunoreactive nerve fibres and RXFP3 mRNA-positive neurons in relation to hippocampal GABA neuron populations. RLN3-positive elements were detected in close-apposition with a substantial population of somatostatin (SST)- and GABA-immunoreactive neurons, and a smaller population of parvalbumin- and calretinin-immunoreactive neurons in different hippocampal areas, consistent with the relative distribution patterns of RXFP3 mRNA and these marker transcripts. In light of the functional importance of the dentate gyrus (DG) hilus in learning and memory, and our anatomical data, we examined the possible influence of RLN3/RXFP3 signaling in this region on spatial memory. Using viral-based Cre/LoxP recombination methods and adult mice with a 'floxed' Rxfp3 gene, we deleted Rxfp3 from DG hilar neurons and assessed spatial memory performance and affective behaviors. Following infusions of an AAV((1/2)) -Cre-IRES-eGFP vector, Cre expression was observed in DG hilar neurons, including SST-positive cells, and in situ hybridization histochemistry for RXFP3 mRNA confirmed receptor deletion relative to levels in floxed-RXFP3 mice infused with an AAV((1/2)) -eGFP (control) vector. RXFP3 depletion within the DG hilus impaired spatial reference memory in an appetitive T-maze task reflected by a reduced percentage of correct choices and increased time to meet criteria, relative to control. In a continuous spontaneous alternation Y-maze task, RXFP3-depleted mice made fewer alternations in the first minute, suggesting impairment of spatial working memory. However, RXFP3-depleted and control mice displayed similar locomotor activity, anxiety-like behavior in light/dark box and elevated-plus maze tests, and learning and long-term memory retention in the Morris water maze. These data indicate endogenous RLN3/RXFP3 signaling can modulate hippocampal-dependent spatial reference and working memory via effects on SST interneurons, and further our knowledge of hippocampal cognitive processing. This article is protected by copyright. All rights reserved.
- Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats. [Journal Article]
- NNeurotoxicology 2017 Jan 15
- Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelli...
Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the hippocampus and cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in PND42 pups, and p-CREB expression in the cerebral cortex was decreased in PND21 pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data indicate that exposure to fluoride and arsenic in early life stage decreases ERK, p-ERK, CREB and p-CREB protein expression in the hippocampus and cerebral cortex of rat offspring at PND21 and PND 42, which may contribute to impaired neurodevelopment following exposure.
- A hepatic stem cell vaccine is superior to an embryonic stem cell vaccine in the prophylaxis and treatment of murine hepatocarcinoma. [Journal Article]
- OROncol Rep 2017 Jan 17
- Stem cells and cancer cells express a common subset of antigens called oncofetal antigens. Theoretically, vaccination with stem cells is effective at boosting the preexisting anticancer immune respon...
Stem cells and cancer cells express a common subset of antigens called oncofetal antigens. Theoretically, vaccination with stem cells is effective at boosting the preexisting anticancer immune response. Herein we describe the efficacy of two stem cell-based vaccines in the prophylaxis and treatment of subcutaneous hepatic tumors transplanted into mice. C57BL/6j mice were vaccinated weekly with either hepatic stem cells (HSCs) or embryonic stem cells (ESCs) for three weeks, followed by a subcutaneous challenge with Hepa 1-6 cells at one week (group 1) or four weeks (group 2) after vaccination. No tumor formation was observed in HSC-vaccinated mice when challenged within one week after vaccination (group 1), but tumors formed in 10% of mice in the ESC-vaccinated group and in 60% of mice in the unvaccinated group. When the long-term memory response was examined (group 2), only 10% of HSC-vaccinated mice and 20% of ESC-vaccinated mice developed macroscopic hepatocarcinomas compared to 60% of the unvaccinated mice. Besides their function as prophylactic vaccines, administration of either HSC or ESC could be a potential treatment for cancer. In mice with subcutaneous hepatocarcinomas, complete clearance of tumor burden was observed in 80% of mice receiving HSC vaccination, but 40% of ESC-vaccinated mice presented with tumors that did not increase in size over time. These data support that HSC is a superior vaccine candidate for durable antitumor protection in this hepatocarcinoma model.
- A perspective on Crocus sativus L (Saffron). Constituent Corcin: a potent water soluble antioxidant and potential therapy for Alzheimer's Disease. [Journal Article]
- JAJ Agric Food Chem 2017 Jan 18
- Alzheimer's Disease (AD) is the most common form of dementia in which the death of brain cells causes memory loss and cognitive decline. Several factors are thought to play roles in the development a...
Alzheimer's Disease (AD) is the most common form of dementia in which the death of brain cells causes memory loss and cognitive decline. Several factors are thought to play roles in the development and course of AD. Existing medical therapies only alleviate and delay cognitive symptoms. Current research has been focused on developing antibodies to remove the targets of β-amyloid (Aβ) and tau protein. This approach has achieved removal of A, however, no long term success to AD patients reported. The biological properties of saffron, the dry stigma of the plant Crocus sativus L., and particularly its main constituent crocin, have been studied extensively for many conditions including dementia and traumatic brain injury. Crocin is a unique antioxidant because it is a water soluble carotenoid. Crocin has shown potential to enhance learning and memory as well as protection of brain cells. We reviewed the research on saffron and crocin which has been published in recent years for its impact on AD as well as crocin's effects on Aβ and tau protein. This review demonstrates that crocin exhibits multi-functional protective activities in the brain and could be a promising safe and natural component for delaying progression of AD.
- Cognitive profiles of patients with early detected and treated congenital hypothyroidism. [Journal Article]
- AAArch Argent Pediatr 2017 02 01; 115(1):12-17
- CONCLUSIONS: Children with congenital hypothyroidism and without mental disability had mild cognitive deficits, which should be taken into account for a comprehensive patient care.
- Molecular classification of tissue from a transformed non-Hogkin's lymphoma case with unexpected long-time remission. [Journal Article]
- EHExp Hematol Oncol 2017; 6:3
- CONCLUSIONS: Thorough analysis of the tumor DNA and RNA documented a branched evolution of the two clinical diagnosed tFL, most likely transformed from an unknown in situ lymphoma. Classification of the malignant tissue for drug-specific resistance did not explain the unexpected long-term remission and potential cure. However, it is tempting to consider the anti-CD20 immunotherapy as the curative intervention in the two independent tumors of this case.
- Differential changes in hippocampal CaMKII and GluA1 activity after memory training involving different levels of adaptive forgetting. [Journal Article]
- LMLearn Mem 2017; 24(2):86-94
- Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic pote...
Phosphorylation of CaMKII and AMPA receptor GluA1 subunit has been shown to play a major role in hippocampal-dependent long-term/reference memory (RM) and in the expression of long-term synaptic potentiation (LTP). In contrast, it has been proposed that dephosphorylation of these proteins could be involved in the opposite phenomenon of hippocampal long-term synaptic depression (LTD) and in adaptive forgetting. Adaptive forgetting allows interfering old memories to be forgotten to give new ones the opportunity to be stored in memory, and in particular in short-term/working memory (WM) that was shown to be very sensitive to proactive interference. To determine the role of CaMKII and GluA1 in adaptive forgetting, we adopted a comparative approach to assess the relative quantity and phosphorylation state of these proteins in the brain of rats trained in one of three radial maze paradigms: a RM task, a WM task involving a high level of adaptive forgetting, or a WM involving a low level of adaptive forgetting. Surprisingly, Western blot analyses revealed that training in a WM task involving a high level of adaptive forgetting specifically increased the expression of AMPA receptor GluA1 subunit and the activity of CaMKII in the dentate gyrus. These results highlight that WM with proactive interference involves mechanisms of synaptic plasticity selectively in the dentate gyrus.
- BDNF regains function in hippocampal long-term potentiation deficits caused by diencephalic damage. [Journal Article]
- LMLearn Mem 2017; 24(2):81-85
- Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magni...
Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage induced by TD in rats. Thus, despite a lack of extensive hippocampal cell loss, diencephalic brain damage down-regulates plastic processes within the hippocampus, likely contributing to impaired hippocampal-dependent behaviors. However, both measures of hippocampal plasticity (LTP, PPF) were restored with brain-derived neurotrophic factor (BDNF), revealing an avenue for neural and behavioral recovery following diencephalic damage.
- The effects of age on the learning and forgetting of primacy, middle, and recency components of a multi-trial word list. [Journal Article]
- JCJ Clin Exp Neuropsychol 2017 Jan 17; :1-13
- The serial position effect reveals that recall of a supraspan list of words follows a predictable pattern, whereby words at the beginning (primacy) and end (recency) of a list are recalled more easil...
The serial position effect reveals that recall of a supraspan list of words follows a predictable pattern, whereby words at the beginning (primacy) and end (recency) of a list are recalled more easily than words in the middle. This effect has typically been studied using single list-learning trials, but in neuropsychology, multi-trial list-learning tests are more commonly used. The current study examined trends in learning for primacy, middle, and recency effects across multiple trials in younger and older age cohorts. Participants were 158 volunteers, including 79 adults aged 17-36 ("younger" group) and 79 adults aged 54-89 years ("older" group). Each participant completed four learning trials and one delayed (5-10 min) recall trial from the Memory Assessment Scales. Scores were divided into primacy (first four words), middle (middle four words), and recency (final four words) scores for all trials. For list acquisition, mixed effects modeling examined the main effects of and interactions between learning slope (logarithmic), age group, and serial position. Rate of learning increased logarithmically over four trials and varied by serial position, with growth of middle and recency word acquisition increasing more rapidly than recall of primacy words; this interaction did not differ by age group. Delayed retention differed according to age group and serial position; both older and younger adults demonstrated similar retention for primacy words, but older adults showed reduced retention for middle and recency words. Although older adults acquired less information across learning trials, the reason for this reduced acquisition was related to initial learning, not to rate of learning over time. Older compared to younger adults were less efficient at transferring middle and recency words from short-term to long-term memory.
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- Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. [Journal Article]
- MPMol Psychiatry 2017 Jan 17
- Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels....
Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.Molecular Psychiatry advance online publication, 17 January 2017; doi:10.1038/mp.2016.250.