Progesterone's Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABAA Activity in the Hippocampus and Cortex

Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progesterone administration would enhance performance in tasks mediated by the hippocampus and cortex, coincident with increasing allopregnanolone concentrations, brain derived neurotrophic factor (BDNF) and/or muscimol binding of PR knock out (PRKO) and wild-type PR replete mice. Experiment 1: Progesterone (4 mg/kg, subcutaneously (SC; n = 12/grp), or oil vehicle control, was administered to gonadally-intact adult male mice PRKO mice and their wild-type counterparts and cognitive behaviors in object recognition, T-maze and water maze was examined. Progesterone, compared to vehicle, when administered post-training increased time investigating novel objects by the PRKO and wild-type mice in the object recognition task. In the T-maze task, progesterone administration to wild-type and PRKO mice had significantly greater number of spontaneous alternations compared to their vehicle-administered counterparts. In the water maze task, PRKO mice administered vehicle spent significantly fewer seconds in the quadrant associated with the escape platform on testing compared to all other groups. Experiment 2: Progesterone administered to wild-type and PRKO mice increased plasma progesterone and allopregnanolone levels (n = 5/group). PRKO mice had higher allopregnanolone levels in plasma and hippocampus, but not cortex, when administered progesterone and compared to wild-type mice. Experiment 3: Assessment of PR binding revealed progesterone administered wild-type mice had significantly greater levels of PRs in the hippocampus and cortex, compared to all other groups (n = 5/group). Wild-type mice administered progesterone, but not vehicle, had increased BDNF levels in the hippocampus, but not the cortex, compared to PRKOs. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABAA agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABAA activity in the hippocampus and cortex.

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Neurotensin receptor levels as a function of brain aging and cognitive performance in the Morris water maze task in the rat

Peptides ◽

10.1016/j.peptides.2006.03.036 ◽

2006 ◽

Vol 27 (10) ◽

pp. 2415-2423 ◽

Cited By ~ 14

Author(s):

W.B. Rowe ◽

S. Kar ◽

M.J. Meaney ◽

R. Quirion

Keyword(s):

Cognitive Performance ◽

Morris Water Maze ◽

Water Maze ◽

Brain Aging ◽

Maze Task ◽

Water Maze Task ◽

Neurotensin Receptor ◽

Morris Water Maze Task

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Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome

Frontiers in Behavioral Neuroscience ◽

10.3389/fnbeh.2021.772734 ◽

2021 ◽

Vol 15 ◽

Author(s):

Cesar Sierra ◽

Ilario De Toma ◽

Lorenzo Lo Cascio ◽

Esteban Vegas ◽

Mara Dierssen

Keyword(s):

Down Syndrome ◽

Object Recognition ◽

Environmental Factors ◽

Mouse Models ◽

Recognition Task ◽

Novel Object Recognition ◽

The Novel ◽

Wild Type ◽

Male And Female ◽

Novel Object

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.

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Sex-specific hippocampus-dependent cognitive deficits and increased neuronal autophagy in DEspR haploinsufficiency in mice

Physiological Genomics ◽

10.1152/physiolgenomics.00044.2008 ◽

2008 ◽

Vol 35 (3) ◽

pp. 316-329 ◽

Cited By ~ 10

Author(s):

Victoria L. M. Herrera ◽

Julius L. Decano ◽

Pia Bagamasbad ◽

Timothy Kufahl ◽

Martin Steffen ◽

...

Keyword(s):

Cerebral Cortex ◽

Cognitive Performance ◽

Cognitive Deficits ◽

Mammalian Target Of Rapamycin ◽

Male Mice ◽

Wild Type ◽

Neuronal Homeostasis ◽

Subcortical Regions ◽

Neuronal Autophagy ◽

Neuronal Vacuolation

Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency ( DEspR−/−) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With the emerging importance of neurogenesis in adulthood, we tested the hypothesis that nonembryonic-lethal DEspR haploinsufficiency ( DEspR+/−) perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here we show that, in male mice only, DEspR-haploinsufficiency impaired hippocampus-dependent visuospatial and associative learning and induced noninflammatory spongiform changes, neuronal vacuolation, and loss in the hippocampus, cerebral cortex, and subcortical regions, consistent with autophagic cell death. In contrast, DEspR+/− females exhibited better cognitive performance than wild-type females and showed absence of neuropathological changes. Signaling pathway analysis revealed DEspR-mediated phosphorylation of activators of autophagy inhibitor mammalian target of rapamycin (mTOR) and dephosphorylation of known autophagy inducers. Altogether, the data demonstrate DEspR-mediated diametrical, sex-specific modulation of cognitive performance and autophagy, highlight cerebral neuronal vulnerability to autophagic dysregulation, and causally link DEspR haploinsufficiency with increased neuronal autophagy, spongiosis, and cognitive decline in mice.

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Adapting the novel-object recognition task to quantify how much attention rodents allocate to motivationally-salient objects

10.1101/495945 ◽

2018 ◽

Author(s):

Iasmina Hornoiu ◽

John Gigg ◽

Deborah Talmi

Keyword(s):

Object Recognition ◽

Recognition Task ◽

Visual Object ◽

Novel Object Recognition ◽

Male Mice ◽

Novel Object ◽

Object Recognition Task ◽

Novel Objects ◽

Motivational Salience ◽

Novel Object Recognition Task

AbstractThe allocation of attention can be modulated by the emotional value of a stimulus. In order to understand the biasing influence of emotion on attention allocation further, we require an animal test of how motivational salience modulates attention. In mice, female odour triggers arousal and elicits emotional responses in males. Here, we determined the extent to which objects labelled with female odour modulated the attention of C57BL/6J male mice. Seven experiments were conducted, using a modified version of the spontaneous Novel Object Recognition task. Attention was operationalised as differential exploration time of identical objects that were labelled with either female mouse odour (O+), a non-social odour, almond odour (Oa) or not labelled with any odour (O-). In some experiments we tested trial unique (novel) objects than never carried an odour (X-). We found that when single objects were presented, as well as when two objects were presented simultaneously (so competed with each other for attention), O+ received preferential attention compared to O-. This result was independent of whether O+ was at a novel or familiar location. When compared with Oa at a novel location, O+ at a familiar location attracted more attention. Compared to X-, O+ received more exploration only when placed at a novel location, but attention to O+ and X- was equivalent when they were placed in a familiar location. These results suggest that C57BL/6J male mice weigh up aspects of odour, object novelty and special novelty for motivational salience, and that, in some instances, female odour elicits more attention (object exploration) compared to other olfactory stimuli and visual object novelty. The findings of this study pave the way to using motivationally-significant odours to modulate the cognitive processes that give rise to novel object recognition.

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Innate Preferences Affect Results of Object Recognition Task in Wild Type and Alzheimer’s Disease Mouse Models

Journal of Alzheimer s Disease ◽

10.3233/jad-215209 ◽

2021 ◽

pp. 1-14

Author(s):

Maria Rosaria Tropea ◽

Giulia Sanfilippo ◽

Federico Giannino ◽

Valentina Davì ◽

Walter Gulisano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Object Recognition ◽

Recognition Task ◽

Wild Type ◽

Behavioral Experiments ◽

Object Recognition Task ◽

Behavioral Paradigm ◽

Shape Influence ◽

Background Object

Background: Object recognition task (ORT) is a widely used behavioral paradigm to assess memory in rodent models, due to its easy technical execution, the lack of aversive stressful stimuli, and the possibility to repeat the test on the same animals. However, mouse exploration might be strongly influenced by a variety of variables. Objective: To study whether innate preferences influenced exploration in male and female wild type mice and the Alzheimer’s disease (AD) model 3xTg. Methods: We first evaluated how object characteristics (material, size, and shape) influence exploration levels, latency, and exploration modality. Based on these findings, we evaluated whether these innate preferences biased the results of ORT performed in wild type mice and AD models. Results: Assessment of Exploration levels, i.e., the time spent in exploring a certain object in respect to the total exploration time, revealed an innate preference for objects made in shiny materials, such as metal and glass. A preference for bigger objects characterized by higher affordance was also evident, especially in male mice. When performing ORT, exploration was highly influenced by these innate preferences. Indeed, both wild type and AD mice spent more time in exploring the metal object, regardless of its novelty. Furthermore, the use of objects with higher affordance such as the cube was a confounding factor leading to “false” results that distorted ORT interpretation. Conclusion: When designing exploration-based behavioral experiments aimed at assessing memory in healthy and AD mice, object characteristics should be carefully evaluated to improve scientific outcomes and minimize possible biases.

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Sema4D/CD100 Deficiency Leads to Superior Performance in Mouse Motor Behavior

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100007101 ◽

2009 ◽

Vol 36 (03) ◽

pp. 349-355 ◽

Cited By ~ 5

Author(s):

Kazunori Yukawa ◽

Tetsuji Tanaka ◽

Noriko Takeuchi ◽

Hiroyuki Iso ◽

Li Li ◽

...

Keyword(s):

Open Field ◽

Water Maze ◽

Motor Behavior ◽

Superior Performance ◽

Adhesive Tape ◽

Wild Type ◽

Maze Task ◽

Embryonic Mouse ◽

Water Maze Task ◽

Deficient Mice

Background:Sema4D/CD100 is a type of class 4 semaphorin, exhibiting crucial rôles in growth cone guidance in developing neurons. Sema4D is widely expressed throughout the central nervous system in embryonic mouse brain, and is selectively localized to oligodendrocytes and myelin in the postnatal brain. However, direct evidence of the actual involvement of Sema4D in the neuronal network development crucial for neurobehavioral performance is still lacking. The present study therefore examined whether Sema4D deficiency leads to abnormal behavioral development.Methods:Both wild-type and Sema4D-deficient mice were subjected to behavioral analyses including open-field, adhesive tape removal, rotarod tests and a water maze task.Results:Open-field tests revealed increased locomotor activity in Sema4D-deficient mice with less percentage of time spent in the center of the field. In both the adhesive tape removal and rotarod tests, which examine motor coordination and balance, Sema4D-deficient mice showed significantly superior performance, suggesting facilitated motor behavior. Both Sema4D-deficient and wild-type mice successfully learnt the water maze task, locating a hidden escape platform, and also showed precise memory for the platform position in probe tests. However, the swimming speed of Sema4D-deficient mice was significantly faster than that of wild-type mice, providing further evidence of their accelerated motor behavior.Conclusion:Our mouse behavioral analyses revealed enhanced motor activity in Sema4D-deficient mice, suggesting the crucial involvement of Sema4D in the neurodevelopmental processes of the central structures mediating motor behavior in mice.

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Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00116.2013 ◽

2014 ◽

Vol 306 (5) ◽

pp. G370-G381 ◽

Cited By ~ 17

Author(s):

Lawrence A. Scheving ◽

Xiuqi Zhang ◽

Oscar A. Garcia ◽

Rebecca F. Wang ◽

Mary C. Stevenson ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Fatty Acid ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Adult Male ◽

Growth Factor Receptor ◽

Male Mice ◽

Wild Type ◽

Cholesterol Levels ◽

Epidermal Growth

Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/ Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/ Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/ Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/ Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/ Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.

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