Compared to results from a generation of neuropharmacological work, the phenotype of mice lacking the oxytocin (OT) peptide gene was remarkably normal. An important component of the current experiments was to assay OT-knockout (OTKO) and wild-type (WT) littermate control mice living under controlled stressful conditions designed to mimic more closely the environment for which the mouse genome evolved. Furthermore, our experimental group was comprised of an all-female population, in contrast to previous studies which have focused on all-male populations. Our data indicated that aggressive behaviors initiated by OTKO during a food deprivation feeding challenge were considerably more intense and diverse than aggressive behaviors initiated by WT. From the measures of continuous social interaction in the intruder paradigm, it emerged that OTKO mice were more offensively aggressive (attacking rumps and tails) than WT. In a test of parental behaviors, OTKO mice were 100% infanticidal while WT were 16% infanticidal and 50% maternal. Finally, 'alpha females' (always OTKO) were identified in each experiment. They were the most aggressive, the first to feed and the most dominant at nesting behaviors. Semi-natural environments are excellent testing environments for elucidating behavioral differences between transgenic mice and their WT littermates which may not be ordinarily discernible. Future studies of mouse group behavior should include examining female groupings in addition to the more usual all-male groups.
Protein kinase CK2 has received a surge of attention in recent years due to the evidence of its overexpression in a variety of solid tumors and multiple myelomas as well as its participation in cell survival pathways. CK2 is also upregulated in the most prevalent and aggressive cancer of brain tissue, glioblastoma multiforme, and in preclinical models, pharmacological inhibition of the kinase has proven successful in reducing tumor size and animal mortality. CK2 is highly expressed in the mammalian brain and has many bona fide substrates that are crucial in neuronal or glial homeostasis and signaling processes across synapses. Full and conditional CK2 knockout mice have further elucidated the importance of CK2 in brain development, neuronal activity, and behavior. This review will discuss recent advances in the field that point to CK2 as a regulator of neuronal functions and as a potential novel target to treat neurological and psychiatric disorders.
Endothelin‐converting enzyme (ECE)‐2 is a metalloprotease that possesses many properties consistent with it being a neuropeptide‐processing enzyme. This protease is found primarily in neural tissues, with high levels of expression in midbrain, cerebellum, hypothalamus, frontal cortex and spinal cord and moderate levels in hippocampus and striatum. To evaluate its role in neural function, mice have been generated lacking this enzyme. Physical appearance, autonomic reflexes, motor co‐ordination, balance, locomotor activity and spontaneous emotional responses appear normal in these knockout (KO) mice. However, these mutants display deficits in learning and memory as evidenced by marked impairment in the Morris water maze. Knockout mice are also deficient in object recognition memory where they show delays in discerning changes in object location and in recognizing the introduction of a novel object. In this study, perseveration appears to interfere with learning and memory. Finally, mutants are impaired in social transmission of food preference where they show poor short‐term memory and perturbations in long‐term memory; the latter can be ameliorated by reminder cues. As ECE‐2 has been implicated in Alzheimer’s disease, the deficits in learning and memory in the KO mice may provide unique insights into processes that may contribute to this disease and possible other disorders of cognition.
The endogenous opioid system has been implicated in sexual behavior, palatable intake, fear, and anxiety. The present study examined whether ovariectomized female transgenic preproenkephalin-knockout (PPEKO) mice and their wild-type and heterozygous controls displayed alterations in fear and anxiety paradigms, sucrose intake, and lordotic behavior. To examine stability of responding, three squads of the genotypes were tested across seasons over a 20-month period. In a fear-conditioning paradigm, PPEKO mice significantly increased freezing to both fear and fear + shock stimuli relative to controls. In the open field, PPEKO mice spent significantly less time and traversed significantly less distance in the center of an open field than wild-type controls. Further, PPEKO mice spent significantly less time and tended to be less active on the light side of a dark-light chamber than controls, indicating that deletion of the enkephalin gene resulted in exaggerated responses to fear or anxiety-provoking environments. These selective deficits were observed consistently across testing squads spanning 20 months and different seasons. In contrast, PPEKO mice failed to differ from corresponding controls in sucrose, chow, or water intake across a range (0.0001-20%) of sucrose concentrations and failed to differ in either lordotic or female approach to male behaviors when primed with estradiol and progesterone, thereby arguing strongly for the selectivity of a fear and anxiety deficit which was not caused by generalized and nonspecific debilitation. These transgenic data strongly suggest that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety.
While the low-density lipoprotein receptor (LDLR) is best known for its role in regulating serum cholesterol, LDLR is expressed in brain, suggesting that it may play a role in CNS function as well. Here, using mice with a null mutation in LDLR (LDLR-/-), we investigated whether the absence of LDLR affects a series of behavioral functions. We also utilized the fact that plasma cholesterol levels can be regulated in LDLR-/-mice by manipulating dietary cholesterol to investigate whether elevated plasma cholesterol might independently affect behavioral performance. LDLR-/-mice showed no major deficits in general sensory or motor function. However, LDLR-/-mice exhibited increased locomotor activity in an open field test without evidence of altered anxiety in either an open field or a light/dark emergence test. By contrast, modulating dietary cholesterol produced only isolated effects. While both C57BL/6J and LDLR-/-mice fed a high cholesterol diet showed increased anxiety in a light/dark task, and LDLR-/-mice fed a high cholesterol diet exhibited longer target latencies in the probe trial of the Morris water maze, no other findings supported a general effect of cholesterol on anxiety or spatial memory.
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