Sex Differences in Retrieval of Context Fear: Behavioral and Neural Mechanisms

The behavioral and neural mechanisms underlying consolidation and retrieval of fear-related memories have been defined over many years. However, the majority of established theories of learning and memory have been based on data derived from predominantly male animals. Throughout this dissertation, I examined how females differ from males behaviorally and in brain regions engaged during retrieval of context fear. In chapter 2, I assessed whether males and females differ in foreground context fear conditioning, generalization to a similar, safe context and determined the neural correlates of retrieval in males and females. I found that females showed higher levels of freezing behavior than males and exhibited greater generalized context fear. Further, I demonstrated that ventral hippocampus is required for retrieval of context fear memories in males and females but that males preferentially engaged dorsal hippocampus following retrieval of context fear memory whereas females preferentially engaged ventral hippocampus and amygdala. If males and females differ in context fear conditioning and engagement of brain regions when memory is recalled at recent time points, they may also differ in retrieval of remote context fear. Therefore, in chapter 3 I examined sex differences in retrieval of remote context fear and determined neural correlates of remote retrieval. I found that females but not males trained with background fear conditioning (tone), show reduced freezing to the context at remote time points. Further, I demonstrated that as in retrieval of recent context fear memories, females preferentially engaged ventral hippocampus and basal amygdala, and also engaged retrosplenial cortex after retrieval of background context fear memory compared with males. Together, chapter 2 and 3 suggest that retrieval and its neural correlates differ between males and females at both recent and remote time points. Therefore, it is likely that males and females engage in distinct cognitive strategies to retrieve context fear. One way to assess sex differences in strategy of retrieval is to examine whether the context-shock association is similarly retrieved in both sexes. In chapter 4 I examined this using a blocking task and extinction paradigm. I show that despite strong context fear memory in both sexes, only males showed blocking to the tone. In extinction, sex differences in patterns of freezing were observed within session where females start off lower in freezing at the beginning of each session and show an increase in freezing throughout the session. While chapters 2-4 provide data to suggest that females differ in hippocampal mechanisms normally activated by retrieval in males, it still remains unclear as to which mechanisms females engage to retrieve context fear memories that may be separate from males. In chapter 5 I use RNA-sequencing as an unbiased approach to identify differential expression of genes in ventral hippocampus of males and females following retrieval and during consolidation of context fear compared with naïve. Despite similar behavior between the sexes during learning and retrieval, I identify a diverse transcriptional profile in ventral hippocampus of males and females following retrieval, during consolidation and at baseline. Collectively, these data determine sex-specific mechanisms associated with retrieval of a context fear memory and move the field closer from pointing out where males and females differ in learning and memory to understanding and defining how and why.PHDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/145811/1/aschmeli_1.pd

The quetiapine active metabolite N-Desalkylquetiapine and the neurotensin NTS1 receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats

Major depressive disorder (MDD) is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that are apparent following one week of quetiapine treatment, and it is possible that the active metabolite N-Desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 are suggestive of antidepressant efficacy, but the effects of a NTS1 receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of the N-Desalkylquetiapine, the neurotensin NTS1 receptor agonist PD14916, quetiapine, the tricylic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate (DRL) 72 s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. The typical antipsychotic drug raclopride decreased both reinforcers and responses. These data suggest that N-Desalklyquetiapine likely contributes to quetiapine’s antidepressant efficacy and identifies NTS1 receptor activation as a potential novel pharmacologic strategy for antidepressant drugs

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Microbial communities may modify how litter quality affects potentia

Examining the contribution of histone modification to sex differences in learning and memory

The epigenome serves as a signal integration platform that encodes information from experience and environment that adds tremendous complexity to the regulation of transcription required for memory, beyond the directions encoded in the genome. To date, our understanding of how epigenetic mechanisms integrate information to regulate gene expression required for memory is primarily obtained from male derived data despite sex-specific life experiences and sex differences in consolidation and retrieval of memory, and in the molecular mechanisms that mediate these processes. In this review, we examine the contribution of chromatin modification to learning and memory in both sexes. We provide examples of how exposure to a number of internal and external factors influence the epigenome in sex-similar and sex-specific ways that may ultimately impact transcription required for memory processes. We also pose a number of key open questions and identify areas requiring further investigation as we seek to understand how histone modifying mechanisms shape memory in females

Characterization Of Interaction Layer In U-Mo-X (X = Nb, Zr) And U-Nb-Zr Vs. Al Diffusion Couples Annealed At 600°C For 10 Hours

U-Mo has thus far proven to be one of the most feasible metallic fuel alloys for use in research and test reactors due to its high density and stability during irradiation. However, an adverse diffusional interaction can occur between the fuel alloy and the Al based matrix. This forms an interaction layer (IL) that has undesirable thermal properties and irradiation behavior leading to accelerated swelling and reduced fuel efficiency. This study focused on the effects of ternary alloying additions on the formation of IL between U based alloys and Al. Diffusion couples of U-8Mo-3Nb, U-7Mo-6Zr, and U-10Nb-4Zr (wt.%) vs. pure Al were assembled and annealed at 600°C for 10 hours. Both thickness and phase constituent analyses were performed via electron microscopy. The major phase constituent of the IL was determined to be the UAl3 intermetallic compound. The Nb and Zr alloying additions did not reduce growth rate of IL (1.3∼1.4 μm/sec1/2) as compared to couples made between binary U-Mo and Al (0.9∼1.8 μm/sec1/2). © (2011) Trans Tech Publications

Potential Annealing Treatments For Tailoring The Starting Microstructure Of Low-Enriched U-Mo Dispersion Fuels To Optimize Performance During Irradiation

Low-enriched uranium-molybdenum (U-Mo) alloy particles dispersed in aluminum alloy (e.g., dispersion fuels) are being developed for application in research and test reactors. To achieve the best performance of these fuels during irradiation, optimization of the starting microstructure may be required by utilizing a heat treatment that results in the formation of uniform, Si-rich interaction layers between the U-Mo particles and Al-Si matrix. These layers behave in a stable manner under certain irradiation conditions. To identify the optimum heat treatment for producing these kinds of layers in a dispersion fuel plate, a systematic annealing study has been performed using actual dispersion fuel samples, which were fabricated at relatively low temperatures to limit the growth of any interaction layers in the samples prior to controlled heat treatment. These samples had different Al matrices with varying Si contents and were annealed between 450 and 525°C for up to 4 h. The samples were then characterized using scanning electron microscopy (SEM) to examine the thickness, composition, and uniformity of the interaction layers. Image analysis was performed to quantify various attributes of the dispersion fuel microstructures that related to the development of the interaction layers. The most uniform layers were observed to form in fuel samples that had an Al matrix with at least 4 wt.% Si and a heat treatment temperature of at least 475°C. © 2011 Elsevier B.V. All rights reserved

Systemic administration of the neurotensin NTS1 receptor agonist PD149163 improves performance on a memory task in naturally deficient male Brown Norway rats

Agonists for neurotensin NTS1 receptor consistently exhibit antipsychotic effects in animal models without producing catalepsy, suggesting that NTS1 receptor agonists may be a novel class of drugs to treat schizophrenia. Moreover, studies utilizing NTS1 agonists have reported improvements in some aspects of cognitive functioning, including prepulse inhibition and learning procedures, that suggest an ability of NTS1 receptor agonists to diminish neurocognitive deficits. The present study sought to assess both baseline delay-induced memory performance and the effects of NTS1 receptor activation on learning and memory consolidation in male Long Evans and Brown Norway rats using a delayed non-match to position radial arm maze task. In the absence of drugs, Brown Norway rats displayed a significant increase in spatial memory errors following a 3, 7, and 24 hour delay, whereas Long Evans rats exhibited an increase in spatial memory errors following only a 7 and 24 hour delay. With Brown Norway rats, administration of PD149163 before or after an information trial significantly reduced errors during a retention trial after a 24 hour delay. Administration of the NTS1/2 receptor antagonist SR142948 prior to the information trial did not affect retention trial errors. These data are consistent with previous findings that Brown Norway rats have natural cognitive deficits and that they may be useful for assessing putative antipsychotic drugs for cognitive efficacy. Moreover, this study supports previous findings suggesting that NTS1 receptor agonists may improve some aspects of cognitive functioning

Data from: Variation in home-field advantage and ability in leaf litter decomposition across successional gradients

1. It is increasingly recognized that interactions between plants and soil (a)biotic conditions can influence local decomposition processes. For example, decomposer communities may become specialized in breaking down litter of plant species that they are associated with, resulting in accelerated decomposition, known as ‘home-field advantage’ (HFA). Also, soils can vary inherently in their capacity to degrade organic compounds, known as ‘ability’. However, we have a poor understanding how environmental conditions drive the occurrence of HFA and ability. 2. Here, we studied how HFA and ability change across three types of successional gradients: coastal sand dunes (primary succession), inland drift sands (primary succession), and ex-arable fields (secondary succession). Across these gradients, litter quality (i.e., nutrient, carbon and lignin contents) increases with successional time for coastal dunes and decreases for the other two gradients. 3. We performed a 12-month reciprocal litter transplant experiment under greenhouse conditions using soils and litters collected from early-, mid-, and late-successional stages of each gradient. 4. We found that HFA and ability did not consistently shift with successional stage for all gradients, but were instead specific for each type of successional gradient. In coastal dunes HFA was positive for early-successional litter, in drift sands it was negative for mid-successional litter, and for ex-arable fields, HFA increased with successional time. Ability of decomposer communities was highest in mid-successional stages for coastal dunes and drift sands, but for ex-arable fields ability decreased throughout with successional time. High HFA was related to high litter C content and soil and organic matter content in soils and to low litter and soil nutrient concentrations. Ability did not consistently occur in successional stages with high or low litter quality. 5. Synthesis: Our findings show that specific environmental conditions, such as changes in litter or soil quality, along environmental gradients can shape the influence of HFA and ability on decomposition. In sites with strong HFA or ability, interactions between plants, litter and decomposer communities will be important drivers of nutrient cycling and hence have the potential to feedback to plant growth