Neurochemical and cognitive changes precede structural abnormalities in the TgF344-AD rat model.

Alzheimer's disease is a progressive neurodegenerative disorder with a decades-long pre-symptomatic phase, substantiating the need for prodromal biomarker development and early intervention. To deconstruct the processes underlying disease progression and identify potential biomarkers, we used neuroimaging techniques with high translational potential to human clinical studies in the TgF344-AD rat model which recapitulates the full spectrum of Alzheimer's neuropathology (progressive amyloid deposition, tauopathy, frank neuronal loss, gliosis, and cognitive dysfunction). We employed longitudinal MRI and magnetic resonance spectroscopy in conjunction with behavioural testing to characterize multiple facets of disease pathology in male and female TgF344-AD rats (n = 26, 14M/12F) relative to wildtype littermates (n = 24, 12M/12F). Testing was performed at 4, 10, 16, and 18 months, covering much of the adult rat lifespan and multiple stages of disease progression. The TgF344-AD model demonstrated impaired spatial reference memory in the Barnes Maze by 4 months of age, followed by neurochemical abnormalities in the hippocampus by 10 months and major structural changes by 16 months. Specifically, TgF344-AD rats displayed increased total choline and lactate, and decreased total creatine, taurine, and N-acetylaspartate to myo-inositol ratio, dentate gyrus hypertrophy, and atrophy in the hippocampus, hypothalamus, and nucleus accumbens. Overall, these findings support the use of MRI and magnetic resonance spectroscopy for the development of non-invasive biomarkers of disease progression, clarify the timing of pathological feature presentation in this model, and contribute to the validation of the TgF344-AD rat as a highly relevant model for pre-clinical Alzheimer's disease research.

Changes in brain structure and function following chronic exposure to inhaled vaporised cannabis during periadolescence in female and male mice: A multimodal MRI study.

BACKGROUND AND AIMS: Social norms and legality surrounding the use of medical and recreational cannabis are changing rapidly. The prevalence of cannabis use in adolescence is increasing. The aim of this study was to assess any sex-based neurobiological effects of chronically inhaled, vaporised cannabis on adolescent female and male mice. METHODS: Female and male mice were exposed daily to vaporised cannabis (10.3% Δ-9-tetrahydrocannabinol [THC] and 0.05% cannabidiol [CBD]) or placebo from postnatal day 23 to day 51. Following cessation of treatment, mice were examined for changes in brain structure and function using noninvasive multimodal magnetic resonance imaging (MRI). Data from voxel-based morphometry, diffusion weighted imaging and rest state functional connectivity were registered to and analysed with a 3D mouse atlas with 139 brain areas. Following imaging, mice were tested for their preference for a novel object. RESULTS: The effects were sexually dimorphic with females showing a unique distribution and inverse correlation between measures of fractional anisotropy and apparent diffusion coefficient localised to the forebrain and hindbrain. In contrast males displayed significant increased functional coupling with the thalamus, hypothalamus and brainstem reticular activating system as compared with controls. Cannabis males also presented with altered hippocampal coupling and deficits in cognitive function. CONCLUSION: Chronic exposure to inhaled vaporised cannabis had significant effects on brain structure and function in early adulthood corroborating much of the literature. Females presented with changes in grey matter microarchitecture, while males showed altered functional connectivity in hippocampal circuitry and deficits in object recognition.

Longitudinal characterization of neuroanatomical changes in the Fischer 344 rat brain during normal aging and between sexes.

Animal models are widely used to study the pathophysiology of disease and to evaluate the efficacy of novel interventions, crucial steps towards improving disease outcomes in humans. The Fischer 344 (F344) wildtype rat is a common experimental background strain for transgenic models of disease and is one of the most frequently used models in aging research. Despite frequency of use, characterization of agerelated neuroanatomical change has not been performed in the F344 rat. To this end, we present a comprehensive longitudinal examination of morphometric change in 73 brain regions and at a voxel-wise level during normative aging in vivo in a mixed-sexcohort of F344 rats. We identified the greatest vulnerability to aging within the cortex, caudoputamen, hindbrain, and internal capsule, while the influence of sex was strongest in the caudoputamen, hippocampus, nucleus accumbens, and thalamus, many of which are implicated in memory and motor control circuits frequently affected by aging and neurodegenerative disease. These findings provide a baseline for neuroanatomical changes associated with aging in male and female F344 rats, to which data from transgenic models or other background strains can be compared.

The utility of maraviroc, an antiretroviral agent used to treat HIV, as treatment for opioid abuse? Data from MRI and behavioural testing in rats.

BACKGROUND: Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/µ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence. METHODS: Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas. RESULTS: Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment. LIMITATIONS: All experiments were performed in male rats only. CONCLUSION: Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.

Longitudinal quantification of metabolites and macromolecules reveals age- and sex-related changes in the healthy Fischer 344 rat brain.

Normal aging is associated with numerous biological changes, including altered brain metabolism and tissue chemistry. In vivo characterization of the neurochemical profile during aging is possible using magnetic resonance spectroscopy, a powerful noninvasive technique capable of quantifying brain metabolites involved in physiological processes that become impaired with age. A prominent macromolecular signal underlies those of brain metabolites and is particularly visible at high fields; parameterization of this signal into components improves quantification and expands the number of biomarkers comprising the neurochemical profile. The present study reports, for the first time, the simultaneous absolute quantification of brain metabolites and individual macromolecules in aging male and female Fischer 344 rats, measured longitudinally using proton magnetic resonance spectroscopy at 7 T. We identified age- and sex-related changes in neurochemistry, with prominent differences in metabolites implicated in anaerobic energy metabolism, antioxidant defenses, and neuroprotection, as well as numerous macromolecule changes. These findings contribute to our understanding of the neurobiological processes associated with healthy aging, critical for the proper identification and management of pathologic aging trajectories. This article is part of the Virtual Special Issue titled COGNITIVE NEUROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect athttps://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Characterizing the human APOE epsilon 4 knock-in transgene in female and male rats with multimodal magnetic resonance imaging.

The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein Ɛ4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers. Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests. The sex differences in behavior and diffusion weighted imaging suggest male carriers of the Ɛ4 allele may be more vulnerable to cognitive and emotional complications compared to female carriers early in life. Conversely, the data may also suggest that female carriers are more resilient to cognitive/emotional problems at this stage of life perhaps due to altered brain volumes and enhanced connectivity.

An MRI-Derived Neuroanatomical Atlas of the Fischer 344 Rat Brain.

This paper reports the development of a high-resolution 3-D MRI atlas of the Fischer 344 adult rat brain. The atlas is a 60 µm isotropic image volume composed of 256 coronal slices with 71 manually delineated structures and substructures. The atlas was developed using Pydpiper image registration pipeline to create an average brain image of 41 four-month-old male and female Fischer 344 rats. Slices in the average brain image were then manually segmented, individually and bilaterally, on the basis of image contrast in conjunction with Paxinos and Watson's (2007) stereotaxic rat brain atlas. Summary statistics (mean and standard deviation of regional volumes) are reported for each brain region across the sample used to generate the atlas, and a statistical comparison of a chosen subset of regional brain volumes between male and female rats is presented. On average, the coefficient of variation of regional brain volumes across all rats in our sample was 4%, with no individual brain region having a coefficient of variation greater than 13%. A full description of methods used, as well as the atlas, the template that the atlas was derived from, and a masking file, can be found on Zenodo at www.zenodo.org/record/3700210. To our knowledge, this is the first MRI atlas created using Fischer 344 rats and will thus provide an appropriate neuroanatomical model for researchers working with this strain.

Treating head injury using a novel vasopressin 1a receptor antagonist.

Arginine vasopressin (AVP) is a chemical signal in the brain that influences cerebral vascular resistance and brain water permeability. Increases in AVP contribute to the pathophysiology of brain edema following traumatic brain injury (TBI). These effects are mediated through AVP V1a receptors that are expressed in cortical and subcortical brain areas. This exploratory study characterizes the effects of a novel, V1a receptor antagonist, AVN576, on behavioral and magnetic resonance imaging (MRI) measures after severe TBI. Male Sprague Dawley rats were impacted twice producing contusions in the forebrain, putative cerebral edema, and cognitive deficits. Rats were treated with AVN576 after initial impact for 5 days and then tested for changes in cognition. MRI was used to assess brain injury, enlargement of the ventricles, and resting state functional connectivity. Vehicle treated rats had significant deficits in learning and memory, enlarged ventricular volumes, and hypoconnectivity in hippocampal circuitry. AVN576 treatment eliminated the enlargement of the lateral ventricles and deficits in cognitive function while increasing connectivity in hippocampal circuitry. These data corroborate the extensive literature that drugs selectively targeting the AVP V1a receptor could be used to treat TBI in the clinic.

Oxycodone Exposure: A Magnetic Resonance Imaging Study in Response to Acute and Chronic Oxycodone Treatment in Rats.

The present study was designed to use blood-oxygen-level dependent (BOLD) imaging to "fingerprint" the change in activity in response to oxycodone (OXY) in drug naïve rats before and after repeated exposure to OXY. It was hypothesized that repeated exposure to OXY would initiate adaptive changes in brain organization that would be reflected in an altered response to opioid exposure. Male rats exposed to OXY repeatedly showed conditioned place preference, evidence of drug-seeking behavior and putative neuroadaptation. As these studies were done on awake rats we discovered it was not possible to image rats continuously exposed to OXY due to motion artifact judged to be withdrawal while in the scanner. To circumvent this problem manganese-enhanced MRI (MEMRI) was used to map the distributed integrated activity pattern resulting from continuous OXY exposure. Rats were administered OXY (2.5 mg/kg, i.p.) during image acquisition and changes in BOLD signal intensity were recorded and the activation and deactivation of integrated neural circuits involved in olfaction and motivation were identified. Interestingly, the circuitry of the mesencephalic dopaminergic system showed little activity to the first exposure of OXY. In the MEMRI study, rats received OXY treatments (2.5 mg/kg, twice daily) for four consecutive days following intraventricular MnCl2. Under isoflurane anesthesia, T1-weighted images were acquired and subsequently analyzed showing activity in the forebrain limbic system, ventral striatum, accumbens, amygdala and hippocampus. These results show brain activity is markedly different when OXY is presented to drug naïve rats versus rats with prior, repeated exposure to drug.

In search of early neuroradiological biomarkers for Parkinson's Disease: Alterations in resting state functional connectivity and gray matter microarchitecture in PINK1 -/- rats.

Parkinson's Disease (PD) is the second most common neurodegenerative disorder, with 60,000 new cases diagnosed each year in the US. There are multiple animal models of PD that attempt to mimic the effects of the disease through genetic alteration. Combined with advanced imaging techniques, these animal models are critical in tracking the neurobiological and behavioral aspects of disease progression and identifying early biomarkers of PD. PTEN-induced putative kinase 1 (PINK1) is a mitochondrial protein kinase involved in protecting neurons from stress-induced mitochondrial dysfunction. A mutation in the PINK1 gene that alters its function can increase the risk for autosomal recessive familial PD and similarly, through genetic deletion of portions of the PINK1 gene in animal models (i.e., "PINK1 knock-out (-/-) rats) produces a progressive loss of dopaminergic neurons in the substantia nigra which is analogous to the pathological hallmarks in human PD patients. In this exploratory study, we used volumetric analysis, resting-state functional connectivity MRI (rs-fcMRI) and diffusion-weighted imaging (DWI) to identify neurobiological differences between wild-type (WT) and PINK1 (-/-) rats. All voxel-based measures for each modality were registered to a rat MRI atlas with 171 segmented and annotated brain regions allowing for the measurement of subtle changes in brain function and architecture that go well beyond typical clinical MRI scanning protocols. Basal ganglia, the mesencephalic dopamine system, the limbic cortex, and the hippocampal complex showed changes in putative gray matter microarchitecture, reflected by shifts in quantitative anisotropy. Rs-fcMRI revealed altered resting state connectivity in many brain areas including the basal ganglia, amygdala, cortex, septum, pons etc. Taken together, these results inform us on a wide range of whole-brain changes occurring in a PD rat model in the absence of cognitive and motor deficits, serving as potential biomarkers and targets for treatment.

Minimum echo time PRESS-based proton observed carbon edited (POCE) MRS in rat brain using simultaneous editing and localization pulses.

PURPOSE: Indirect 13 C MRS by proton-observed carbon editing (POCE) is a powerful method to study brain metabolism. The sensitivity of POCE-MRS can be enhanced through the use of short TEs, which primarily minimizes homonuclear J-evolution related losses; previous POCE-MRS implementations use longer than optimal echo times due to sequence limitations, or short TE image selected in vivo spectroscopy-based multi-shot acquisitions for 3D localization. To that end, this paper presents a novel single-shot point resolved spectroscopy (PRESS)-localized POCE-MRS sequence that involves the application of simultaneous editing and localization pulses (SEAL)-PRESS, allowing the TE to be reduced to a theoretically optimal value of ∼ 1/JHC . METHODS: The optimized SEAL-PRESS sequence was first evaluated in simulation and in phantom; next, the sequence was validated with dynamic in vivo POCE-MRS performed in a rat preparation during a 1,6-13 C2 -Glc infusion, and on a microwave fixed rat brain following a 2-hour [1,6-13 C2 ]-Glc infusion. POCE spectra from the SEAL-PRESS sequence were compared against a previously described 12.6-ms PRESS-POCE sequence utilizing a classical carbon editing scheme. RESULTS: The SEAL-PRESS sequence provides > 95% editing efficiency, optimal sensitivity, and localization for POCE MRS with an overall sequence TE of 8.1 ms. Signal amplitude of 13 C-labeled metabolites Glu-H4, Gln-H4, Glx-H3, Glc-H6 +Glx-H2, and Asp-H2 were shown to be improved by >17% relative to a 12.6-ms PRESS-POCE sequence in vivo. CONCLUSION: We report for the first time, a single-shot PRESS-localized and edited 8.1-ms TE POCE-MRS sequence with optimal sensitivity, editing efficiency, and localization.

In vivo proton observed carbon edited (POCE) 13 C magnetic resonance spectroscopy of the rat brain using a volumetric transmitter and receive-only surface coil on the proton channel.

PURPOSE: In vivo carbon-13 (13 C) MR spectroscopy (MRS) is capable of measuring energy metabolism and neuroenergetics, noninvasively in the brain. Indirect (1 H-[13 C]) MRS provides sensitivity benefits compared with direct 13 C methods, and normally includes a 1 H surface coil for both localization and signal reception. The aim was to develop a coil platform with homogenous B1+ and use short conventional pulses for short echo time proton observed carbon edited (POCE) MRS. METHODS: A 1 H-[13 C] MRS coil platform was designed with a volumetric resonator for 1 H transmit, and surface coils for 1 H reception and 13 C transmission. The Rx-only 1 H surface coil nullifies the requirement for a T/R switch before the 1 H preamplifier; the highpass filter and preamplifier can be placed proximal to the coil, thus minimizing sensitivity losses inherent with POCE-MRS systems described in the literature. The coil platform was evaluated with a PRESS-POCE sequence (TE = 12.6 ms) on a rat model. RESULTS: The coil provided excellent localization, uniform spin nutation, and sensitivity. 13 C labeling of Glu-H4 and Glx-H3 peaks, and the Glx-H2 peaks were observed approximately 13 and 21 min following the infusion of 1-13 C glucose, respectively. CONCLUSION: A convenient and sensitive platform to study energy metabolism and neurotransmitter cycling is presented. Magn Reson Med 79:628-635, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

System-specific activity in response to Δ9 -tetrahydrocannabinol: a functional magnetic resonance imaging study in awake male rats.

The aim of this study was to assess the effects of two doses of Δ9 -tetrahydrocannabinol (THC, cannabis' main psychoactive agent) and vehicle on blood-oxygen-level dependent (BOLD) activity in drug-naïve, awake rats, in an effort to obtain a THC-specific map of activation in clinically-relevant regions and systems. Intraperitoneal injections of low dose of THC resulted in increased positive and negative BOLD signals compared to vehicle and high dose in areas rich in cannabinoid receptor 1, as well as throughout the pain and hippocampal neural systems. These results offer unique maps of activity, or 'fingerprints', associated with systemic THC administration, allowing for further comparisons with either additional doses or compounds, or between THC administration modalities (i.e. systemic vs. ingested vs. inhaled), which ultimately adds to the translatability assessment of THC-induced BOLD between animal and human studies.

A non-invasive restraining system for awake mouse imaging.

BACKGROUND: Preclinical neuroimaging allows for the assessment of brain anatomy, connectivity and function in laboratory animals, such as mice and rats. Most of these studies are performed under anesthesia to avoid movement during the scanning sessions. METHOD: Due to the limitations associated with anesthetized imaging, recent efforts have been made to conduct rodent imaging studies in awake animals, habituated to the restraint systems used in these instances. As of now, only one such system is commercially available for mouse scanning (Animal Imaging Research, Boston, MA, USA) integrating the radiofrequency coil electronics with the restraining element, an approach which, although effective in reducing head motion during awake imaging, has some limitations. In the current report, we present a novel mouse restraining system that addresses some of these limitations. RESULTS/COMPARISON TO OTHER METHODS: The effectiveness of the restraining system was evaluated in terms of three-dimensional linear head movement across two consecutive functional MRI scans (total 20min) in 33 awake mice. Head movement was minimal, recorded in roughly 12% of the time-series. Respiration rate during the acclimation procedure dropped while the bolus count remained unchanged. Body movement during functional acquisitions did not have a significant effect on magnetic field (B0) homogeneity. CONCLUSION/NOVELTY: Compared to the commercially available system, the benefit of the current design is two-fold: 1) it is compatible with a range of commercially-available coils, and 2) it allows for the pairing of neuroimaging with other established techniques involving intracranial cannulation (i.e. microinfusion and optogenetics).

A chronic in situ coil system adapted for intracerebral stimulation during MRI in rats.

BACKGROUND: We describe the fabrication and performance of a chronic in situ coil system designed to allow focal brain stimulation in rats while acquiring functional MRI data. NEW METHOD: An implantable receive-only surface radiofrequency coil (iCoil) was designed to be fitted subcutaneously, directly onto to the rat skull surface during the intracerebral cannulation procedure. The coil is fixed in place using acrylic dental cement anchored to four screws threaded into the skull. To demonstrate the use of this coil system in situ, whole-brain functional MRI scans were acquired during various stimuli, including intracranial microinfusions of bicuculline and morphine in the prefrontal cortex and ventral tegmental area, respectively. RESULTS/COMPARISON TO OTHER METHODS: SNR performance of the iCoil was superior to three commercially-available coils, in some instances by a factor of two. Widespread BOLD activation was observed in response to bicuculline and morphine microinfusions. CONCLUSION: A new approach was demonstrated for high-SNR MR imaging of the brain in rats with intracranial implants using an implantable surface coil. This approach enables mapping the functional response to highly targeted stimuli such as intracranial microinfusions.

BOLD Imaging in Awake Wild-Type and Mu-Opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone.

Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, and Mu (µ) opioid receptor knock-outs (MuKO) in response to oxycodone (OXY). Using a segmented, annotated MRI mouse atlas and computational analysis, patterns of integrated positive and negative BOLD activity were identified across 122 brain areas. The pattern of positive BOLD showed enhanced activation across the brain in WT mice within 15 min of intraperitoneal administration of 2.5 mg of OXY. BOLD activation was detected in 72 regions out of 122, and was most prominent in areas of high µ opioid receptor density (thalamus, ventral tegmental area, substantia nigra, caudate putamen, basal amygdala, and hypothalamus), and focus on pain circuits indicated strong activation in major pain processing centers (central amygdala, solitary tract, parabrachial area, insular cortex, gigantocellularis area, ventral thalamus primary sensory cortex, and prelimbic cortex). Importantly, the OXY-induced positive BOLD was eliminated in MuKO mice in most regions, with few exceptions (some cerebellar nuclei, CA3 of the hippocampus, medial amygdala, and preoptic areas). This result indicates that most effects of OXY on positive BOLD are mediated by the µ opioid receptor (on-target effects). OXY also caused an increase in negative BOLD in WT mice in few regions (16 out of 122) and, unlike the positive BOLD response the negative BOLD was only partially eliminated in the MuKO mice (cerebellum), and in some case intensified (hippocampus). Negative BOLD analysis therefore shows activation and deactivation events in the absence of the µ receptor for some areas where receptor expression is normally extremely low or absent (off-target effects). Together, our approach permits establishing opioid-induced BOLD activation maps in awake mice. In addition, comparison of WT and MuKO mutant mice reveals both on-target and off-target activation events, and set an OXY brain signature that should, in the future, be compared to other µ opioid agonists.

Circadian time-place (or time-route) learning in rats with hippocampal lesions.

Circadian time-place learning (TPL) is the ability to remember both the place and biological time of day that a significant event occurred (e.g., food availability). This ability requires that a circadian clock provide phase information (a time tag) to cognitive systems involved in linking representations of an event with spatial reference memory. To date, it is unclear which neuronal substrates are critical in this process, but one candidate structure is the hippocampus (HPC). The HPC is essential for normal performance on tasks that require allocentric spatial memory and exhibits circadian rhythms of gene expression that are sensitive to meal timing. Using a novel TPL training procedure and enriched, multidimensional environment, we trained rats to locate a food reward that varied between two locations relative to time of day. After rats acquired the task, they received either HPC or SHAM lesions and were re-tested. Rats with HPC lesions were initially impaired on the task relative to SHAM rats, but re-attained high scores with continued testing. Probe tests revealed that the rats were not using an alternation strategy or relying on light-dark transitions to locate the food reward. We hypothesize that transient disruption and recovery reflect a switch from HPC-dependent allocentric navigation (learning places) to dorsal striatum-dependent egocentric spatial navigation (learning routes to a location). Whatever the navigation strategy, these results demonstrate that the HPC is not required for rats to find food in different locations using circadian phase as a discriminative cue.

High estrogen and chronic haloperidol lead to greater amphetamine-induced BOLD activation in awake, amphetamine-sensitized female rats.

The ovarian hormone estrogen has been implicated in schizophrenia symptomatology. Low levels of estrogen are associated with an increase in symptom severity, while exogenous estrogen increases the efficacy of antipsychotic medication, pointing at a possible interaction between estrogen and the dopaminergic system. The aim of this study is to further investigate this interaction in an animal model of some aspects of schizophrenia using awake functional magnetic resonance imaging. Animals receiving 17ß-estradiol and haloperidol were scanned and BOLD activity was assessed in response to amphetamine. High 17ß-estradiol replacement and chronic haloperidol treatment showed increased BOLD activity in regions of interest and neural networks associated with schizophrenia (hippocampal formations, habenula, amygdala, hypothalamus etc.), compared with low, or no 17ß-estradiol. These data show that chronic haloperidol treatment has a sensitizing effect, possibly on the dopaminergic system, and this effect is dependent on hormonal status, with high 17ß-estradiol showing the greatest BOLD increase. Furthermore, these experiments further support the use of imaging techniques in studying schizophrenia, as modeled in the rat, but can be extended to addiction and other disorders.

Changes in brain volume in response to estradiol levels, amphetamine sensitization and haloperidol treatment in awake female rats.

Estrogen has been shown to further ameliorate symptoms when administered in conjunction with antipsychotics in patients with schizophrenia. We have previously shown that chronic haloperidol (HAL) treatment reduces amphetamine (AMPH)-induced locomotor activity in AMPH-sensitized rats, but only when paired with high levels of the estrogen, 17-ß estradiol. In addition, we reported estradiol-dependent responses to AMPH in AMPH-sensitized rats as measured by functional magnetic resonance imaging. It is thus clear that estradiol and antipsychotics both affect the rat brain, however the mechanism by which this occurs is unknown. The aim of the current study was to assess this interaction by investigating the effects of estradiol, AMPH and HAL on brain volume changes in awake female rats. Repeated exposure to AMPH resulted in an overall reduction in brain volume, regardless of hormonal status (i.e. no, low or high estradiol). Similarly, chronic HAL treatment further reduced brain volume compared to acute treatment. Hormonal status affected hippocampal volume with rats receiving low estradiol replacement showing larger volume; this difference was no longer significant after repeated exposure to AMPH. Finally, we found changes in volume in response to AMPH throughout hippocampal components (i.e. CA1-CA3 and dentate) as well as components of the mesocortical system. In conclusion, brain volume seems to be influenced by hormonal status, as well as exposure to AMPH and haloperidol treatment. These findings implicate areas where estradiol, amphetamine and antipsychotics may be producing volumetric changes in the brain, pointing the way to where future studies should focus.