Escalation of Wheel Running: An Animal Model of Non-Drug Addiction

Animal studies using the self-administration paradigm suggest that duration of drug access (Ahmed, 2005) and individual phenotype (Piazza, Deminiere, Le Moal and Simon, 1989) are important factors in the development of drug addiction. Wheel running in rats has been proposed as a model to study non-drug addictions (Eikelboom & Lattanzio, 2003). When first given ad lib wheel access, young male rats initially run at low levels (about 1000 wheel turns per night) and gradually increase this distance to high levels (about 5000 wheel turns per night) (Afonso and Eikelboom, 2003). Like with self-administration, duration of wheel access has been found to be critical to the development of this excessive running (Eikelboom & Lattanzio, 2003). At this point it is not clear how individual phenotype and duration of access interact to result in the excessive behaviour seen in addiction. Understanding the mechanisms involved in this increase may shed light on the transition from regulated levels of behaviour to high and uncontrollable levels. The three experiments in this thesis manipulated the duration and time of wheel access to determine how these variables affect final running levels. In Experiment 1, 32 male rats had either 30, 45, 60 or 90 minutes of nightly wheel access either starting at 13:00 (one hour after lights went out) or ending at 14:30 for 24 days. Running increased only in the 90 minute group. Rats introduced to the wheel at 13:00 ran more and increased their running more than rats introduced later. This difference was determined to be due to baseline running differences prior to restricted access. In Experiment 2 duration of nightly wheel access was held constant (45 minutes) but time of wheel introduction was manipulated. From lights out to 6 hours after lights off all groups ran equally and did not increase their running significantly. In Experiment 3 time of wheel introduction was held constant and 72 rats were given either 30, 60, 90, or 180 minutes of wheel access 1 hour after lights out. While running increased for all groups the 180 minute group showed the largest increase. Individual correlations suggested that final running levels could be predicted by the mean of the first 4 days of running. A multiple-regression using both duration of access, and the mean of first 4 days suggested that both are important in final running levels. Similar to drug addiction, both duration of access and individual differences may be important in non-drug addictions

Divergent effects of repeated cocaine and novel environment exposure on locus coeruleus c‐fos expression and brain catecholamine concentrations in rats

IntroductionChronic administration of cocaine causes a disinhibited, hyperexploratory response to novel environments. As the norepinephrine (NE) system regulates exploration and is dysregulated following cocaine exposure, we hypothesized that this cocaine‐mediated hyperexploratory response is associated with increased locus coeruleus (LC) reactivity.MethodsTo test this hypothesis, we used dual fluorescent in situ hybridization immunofluorescence to analyze novelty‐induced c‐fos and tyrosine hydroxylase expression in the LC and high‐pressure liquid chromatography to measure dopamine (DA) and NE concentrations in key catecholamine projection regions following exposure to cocaine.ResultsRepeated cocaine exposure followed by a 14‐day drug‐free period increased exploration of novel environments, replicating previous findings. Novelty exposure increased LC c‐fos expression, increased anterior cingulate NE, and decreased ventral tegmental area DA. Cocaine exposure decreased amygdala (AMY) DA, but had no effect on LC c‐fos expression or NE in any tested brain region. No interactions between cocaine and novelty were found. Open arm exploration was positively correlated with LC c‐fos expression and NE concentrations in both the anterior cingulate and nucleus accumbens, and negatively correlated with AMY DA concentration.ConclusionsOur findings confirm that exposure to novel environments increases LC activity and NE in the anterior cingulate cortex, that long‐term exposure to cocaine dysregulates AMY DA, and that disinhibited exploration in novel environments correlates with NE and DA in regions that modulate risk‐taking and avoidance behavior. Further studies investigating the effects of cocaine on brain catecholamine systems are important in understanding the long‐lasting effects of cocaine on brain function.Chronic cocaine exposure causes a long‐lasting, disinhibited, hyperexploratory phenotype. This effect may be partially driven by changes in locus coeruleus (LC) function, as LC activation in response to novel environments is correlated with this disinhibited exploratory behavior.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148353/1/brb31222_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148353/2/brb31222.pd

Experience-dependent persistent expression of zif268 during rest is preserved in the aged dentate gyrus

BACKGROUND: Aging is typically accompanied by memory decline and changes in hippocampal function. Among these changes is a decline in the activity of the dentate gyrus (DG) during behavior. Lasting memory, however, is thought to also require recapitulation of recent memory traces during subsequent rest – a phenomenon, termed memory trace reactivation, which is compromised in hippocampal CA1 with progressive age. This process has yet to be assessed in the aged DG, despite its prominent role in age-related memory impairment. Using zif268 transcription to measure granule cell recruitment, DG activity in adult and aged animals was assessed both during spatial exploration and as animals remained at rest in the home cage in order to detect potential memory-related replay. RESULTS: Consistent with the observation of memory trace reactivation in DG, the probability that an individual granule cell transcribes zif268 during rest in the animal’s home cage is increased by recent experience in a novel environment. Surprisingly, a comparable increase was observed in the probability of granule cells in the aged DG expressing zif268 during rest. Moreover, no significant age-related difference was observed in the number of granule cells expressing zif268 during rest. Thus, the number and pattern of granule cell expression of zif268 during rest is preserved in aged animals, despite a significant decline in exploration-related zif268 expression. CONCLUSIONS: These data lead to the hypothesis that the input the aged DG receives from backprojections from CA3 (the region widely hypothesized to mediate reactivation) remains functionally intact despite loss of innervation from the perforant path

Ubiquitous Spin Freezing in the Superconducting State of UTe2

In most superconductors electrons form Cooper pairs in a spin-singlet state mediated by either phonons or by long-range interactions such as spin fluctuations. The superconductor UTe$_2$ is a rare material wherein electrons are believed to form pairs in a unique spin-triplet state with potential topological properties. While spin-triplet pairing may be mediated by ferromagnetic or antiferromagnetic fluctuations, experimentally, the magnetic properties of UTe$_2$ are unclear. By way of muon spin rotation/relaxation ($\mu$SR) measurements on independently grown UTe$_2$ single crystals we demonstrate the existence of magnetic clusters that gradually freeze into a disordered spin frozen state at low temperatures. Our findings suggest that inhomogeneous freezing of magnetic clusters is linked to the ubiquitous residual linear term in the temperature dependence of the specific heat ($C$) and the low-temperature upturn in $C/T$ versus $T$. The omnipresent magnetic inhomogeneity has potential implications for experiments aimed at establishing the intrinsic low-temperature properties of UTe$_2$.Comment: 33 pages, 9 figure