The SIGMA rat brain templates and atlases for multimodal MRI data analysis and visualization.

Preclinical imaging studies offer a unique access to the rat brain, allowing investigations that go beyond what is possible in human studies. Unfortunately, these techniques still suffer from a lack of dedicated and standardized neuroimaging tools, namely brain templates and descriptive atlases. Here, we present two rat brain MRI templates and their associated gray matter, white matter and cerebrospinal fluid probability maps, generated from ex vivo [Formula: see text]-weighted images (90 µm isotropic resolution) and in vivo T2-weighted images (150 µm isotropic resolution). In association with these templates, we also provide both anatomical and functional 3D brain atlases, respectively derived from the merging of the Waxholm and Tohoku atlases, and analysis of resting-state functional MRI data. Finally, we propose a complete set of preclinical MRI reference resources, compatible with common neuroimaging software, for the investigation of rat brain structures and functions.

The dynamics of stress: a longitudinal MRI study of rat brain structure and connectome.

Stress is a well-established trigger for a number of neuropsychiatric disorders, as it alters both structure and function of several brain regions and its networks. Herein, we conduct a longitudinal neuroimaging study to assess how a chronic unpredictable stress protocol impacts the structure of the rat brain and its functional connectome in both high and low responders to stress. Our results reveal the changes that stress triggers in the brain, with structural atrophy affecting key regions such as the prelimbic, cingulate, insular and retrosplenial, somatosensory, motor, auditory and perirhinal/entorhinal cortices, the hippocampus, the dorsomedial striatum, nucleus accumbens, the septum, the bed nucleus of the stria terminalis, the thalamus and several brain stem nuclei. These structural changes are associated with increasing functional connectivity within a network composed by these regions. Moreover, using a clustering based on endocrine and behavioural outcomes, animals were classified as high and low responders to stress. We reveal that susceptible animals (high responders) develop local atrophy of the ventral tegmental area and an increase in functional connectivity between this area and the thalamus, further spreading to other areas that link the cognitive system with the fight-or-flight system. Through a longitudinal approach we were able to establish two distinct patterns, with functional changes occurring during the exposure to stress, but with an inflection point after the first week of stress when more prominent changes were seen. Finally, our study revealed differences in functional connectivity in a brainstem-limbic network that distinguishes resistant and susceptible responders before any exposure to stress, providing the first potential imaging-based predictive biomarkers of an individual's resilience/vulnerability to stressful conditions.

White matter changes in microstructure associated with a maladaptive response to stress in rats.

In today's society, every individual is subjected to stressful stimuli with different intensities and duration. This exposure can be a key trigger in several mental illnesses greatly affecting one's quality of life. Yet not all subjects respond equally to the same stimulus and some are able to better adapt to them delaying the onset of its negative consequences. The neural specificities of this adaptation can be essential to understand the true dynamics of stress as well as to design new approaches to reduce its consequences. In the current work, we employed ex vivo high field diffusion magnetic resonance imaging (MRI) to uncover the differences in white matter properties in the entire brain between Fisher 344 (F344) and Sprague-Dawley (SD) rats, known to present different responses to stress, and to examine the effects of a 2-week repeated inescapable stress paradigm. We applied a tract-based spatial statistics (TBSS) analysis approach to a total of 25 animals. After exposure to stress, SD rats were found to have lower values of corticosterone when compared with F344 rats. Overall, stress was found to lead to an overall increase in fractional anisotropy (FA), on top of a reduction in mean and radial diffusivity (MD and RD) in several white matter bundles of the brain. No effect of strain on the white matter diffusion properties was observed. The strain-by-stress interaction revealed an effect on SD rats in MD, RD and axial diffusivity (AD), with lower diffusion metric levels on stressed animals. These effects were localized on the left side of the brain on the external capsule, corpus callosum, deep cerebral white matter, anterior commissure, endopiriform nucleus, dorsal hippocampus and amygdala fibers. The results possibly reveal an adaptation of the SD strain to the stressful stimuli through synaptic and structural plasticity processes, possibly reflecting learning processes.

[Stress and psychotic transition: A literature review]. / Stress et transition psychotique : revue de la littérature.

BACKGROUND: Psychiatric disorders are consistent with the gene x environment model, and non-specific environmental factors such as childhood trauma, urbanity, and migration have been implicated. All of these factors have in common to dysregulate the biological pathways involved in response to stress. Stress is a well-known precipitating factor implicated in psychiatric disorders such as depression, bipolar disorder, anxiety, and possibly schizophrenia. More precisely, psychosocial stress induces dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) and could modify neurotransmission, which raises the question of the involvement of stress-related biological changes in psychotic disorders. Indeed, the literature reveals dysregulation of the HPA axis in schizophrenia. This dysregulation seems to be present in the prodromal phases (UHR subjects for ultra-high risk) and early schizophrenia (FEP for first episode psychosis). Thus, and following the stress-vulnerability model, stress could act directly on psychotic onset and precipitate the transition of vulnerable subjects to a full-blown psychosis. OBJECTIVE: The present paper reviews the literature on stress and onset of schizophrenia, with consideration for the causal role vs. associated role of HPA axis dysregulation in schizophrenia and the factors that influence it, in particular during prodromal and earlier phases. We also discuss different methods developed to measure stress in humans. METHODOLOGY: We performed a bibliographic search using the keywords 'cortisol', 'glucocorticoid', 'HPA' with 'UHR', 'CHR', 'at-risk mental state', 'first episode psychosis', 'schizotypal', 'prodromal schizophrenia' in Medline, Web of Knowledge (WOS), and EBSCO completed by a screening of the references of the selected articles. RESULTS: Stress has been studied for many years in schizophrenia, either by subjective methods (questionnaires), or objective methods (standardized experimental protocols) with biological sampling and/or brain imaging methods. These methods have suggested a link between dysregulation of the HPA axis and psychotic symptoms both through abnormal basal levels of cortisol and flattened reactivity to social stress. Imaging results suggest indirect modifications, including abnormal pituitary or hippocampal volume. Several factors dysregulating the HPA axis have also been highlighted, such as consumption of drugs (i.e. cannabis), childhood trauma or genetic factors (such as COMT, or MTHFR variants). Psychological stress induces subcortical dopaminergic activation attributable to hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This dysregulation is present in the prodromal phase (UHR) in patients who have experienced a first psychotic episode (FEP) and in siblings of schizophrenic patients. Stress dysregulation is a plausible hypothesis to understand the psychosis onset. DISCUSSION: The effect of stress on brain pathways could participate to the mechanisms underlying the onset of psychotic symptoms, both as a precipitating factor and as a marker of a predisposing vulnerability. This dysregulation fits into the gene x environment model: in subjects with genetic predispositions, stressful environmental factors can modify biological pathways implicated in psychiatric disorders, promoting the emergence of symptoms. However, many confounding factors obscure the literature, and further studies are needed in schizophrenic patients, UHR and FEP patients to clarify the precise role of stress in psychotic transition. Identification of stress biomarkers could help diagnosis and prognosis, and pave the way for specific care strategies based on stress-targeted therapies.

Hyper-responsivity to stress in rats is associated with a large increase in amygdala volume. A 7T MRI study.

Stress is known to precipitate psychiatric disorders in vulnerable people. Individual differences in the stress responsivity can dramatically affect the onset of these illnesses. Animal models of repeated stress represent valuable tools to identify region-specific volumetric changes in the brain. Here, using high resolution 7T MRI, we found that amygdala is the most significant parameter for distinction between F344 and SD rats known to have differential response to stress. A significant substantial increase (45%) was found in the amygdala volume of rats that do not habituate to the repeated stress procedure (F344 rats) compared to SD rats. This strain-specific effect of stress was evidenced by a significant strain-by-stress interaction. There were no significant strain differences in the volumes of hippocampi and prefrontal cortices though stress produces significant reductions of smaller amplitude in the medial prefrontal cortex (mPFC) (9% and 12%) and dorsal hippocampus (5% and 6%) in both strains. Our data further demonstrate the feasibility and relevance of high isotropic resolution structural ex vivo 7T MRI in the study of the brain effects of stress in small animals. Neuroimaging is a valuable tool to follow up brain volumetric reorganization during the stress response and could also be easily used to test pharmacological interventions to prevent the deleterious effects of stress.

Acute tianeptine treatment selectively modulates neuronal activation in the central nucleus of the amygdala and attenuates fear extinction.

Antidepressant drugs are commonly prescribed treatments for anxiety disorders, and there is growing interest in understanding how these drugs impact fear extinction because extinction learning is pivotal to successful exposure-based therapy (EBT). A key objective within this domain is understanding how antidepressants alter the activation of specific elements of the limbic-based network that governs such fear processing. Chronic treatment with the antidepressant tianeptine has been shown to reduce the acquisition of extinction learning in rats, yet the drug's acute influence on activation in prefrontal and amygdalar regions, and on extinction learning are not well understood. To assess its influence on cellular activation, rats were injected with tianeptine and Fos immunoreactivity was measured in these regions. Acute tianeptine treatment selectively altered Fos expression within subdivisions of the central nucleus of the amygdala (CEA) in a bidirectional manner that varied in relation to ongoing activation within the capsular subdivision and its prefrontal and intra-amygdalar inputs. This pattern of results suggests that the drug can conditionally modulate the activation of CEA subdivisions, which contain microcircuits strongly implicated in fear processing. The effect of acute tianeptine was also examined with respect to the acquisition, consolidation and expression of fear extinction in rats. Acute tianeptine attenuated extinction learning as well as the recall of extinction memory, which underscores that acute dosing with the drug could alter learning during EBT. Together these findings provide a new perspective for understanding the mechanism supporting tianeptine's clinical efficacy, as well as its potential influence on CEA-based learning mechanisms.

The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation.

Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.

One-carbon metabolism and schizophrenia: current challenges and future directions.

Schizophrenia is a heterogeneous disease generally considered to result from a combination of heritable and environmental factors. Although its pathophysiology has not been fully determined, biological studies support the involvement of several possible components including altered DNA methylation, abnormal glutamatergic transmission, altered mitochondrial function, folate deficiency and high maternal homocysteine levels. Although these factors have been explored separately, they all involve one-carbon (C1) metabolism. Furthermore, C1 metabolism is well positioned to integrate gene-environment interactions by influencing epigenetic regulation. Here, we discuss the potential roles of C1 metabolism in the pathophysiology of schizophrenia. Understanding the contribution of these mechanisms could yield new therapeutic approaches aiming to counteract disease onset or progression.

Peri-pubertal maturation after developmental disturbance: a model for psychosis onset in the rat.

Schizophrenia is thought to be associated with abnormalities during neurodevelopment although those disturbances usually remain silent until puberty; suggesting that postnatal brain maturation precipitates the emergence of psychosis. In an attempt to model neurodevelopmental defects in the rat, brain cellular proliferation was briefly interrupted with methylazoxymethanol (MAM) during late gestation at embryonic day 17 (E17). The litters were explored at pre- and post-puberty and compared with E17 saline-injected rats. We measured spontaneous and provoked locomotion, working memory test, social interaction, and prepulse inhibition (PPI). As compared with the saline-exposed rats, the E17 MAM-exposed rats exhibited spontaneous hyperactivity that emerged only after puberty. At adulthood, they also exhibited hypersensitivity to the locomotor activating effects of a mild stress and a glutamatergic N-methyl-D-aspartate receptor antagonist (MK-801), as well as PPI deficits whereas before puberty no perturbations were observed. In addition, spatial working memory did not undergo the normal peri-pubertal maturation seen in the sham rats. Social interaction deficits were observed in MAM rats, at both pre- and post-puberty. Our study further confirms that transient prenatal disruption of neurogenesis by MAM at E17 is a valid behavioral model for schizophrenia as it is able to reproduce some fundamental features of schizophrenia with respect to both phenomenology and temporal pattern of the onset of symptoms and deficits.

Opposite behaviours in the forced swimming test are linked to differences in spatial working memory performances in the rat.

Despite consistent evidence of an association between depression and impaired memory performance, only a few studies have investigated memory processes in animal models of depression. The aim of the present study was to determine if rats selected for marked differences in their immobility response in the forced swimming test (FST, i.e. high-immobility, [HI] and low-immobility [LI] rats) exhibit differences in spatial and non-spatial memory performances. In a classic radial maze elimination task, we observed that HI rats made significantly more errors than LI rats, and their first error appeared significantly earlier. In a delayed spatial win-shift procedure where rats have to hold spatially relevant information in working memory across a 30 min delay, HI rats tended initially to perform more poorly than LI rats. HI rats made more across-phase errors, the occurrence of the first error was earlier and by the end of the experiment the differences between the two groups disappeared. Thus, HI rats present more difficulties to learn the rules in a spatial task and show weaker performances in spatial working memory in comparison to LI rats. On the other hand, performances in the two groups of animals were similar in a non-spatial task, the object recognition task. Complementary behavioral data indicate that the differences observed between the two groups are not attributable to opposite locomotor activities or to different levels of anxiety. Overall we can conclude that opposite swimming behavior in the FST could parallel some differences in cognitive performances, more specifically linked to spatial working memory.

Working memory deficits in adult rats after prenatal disruption of neurogenesis.

We investigated the cognitive consequences of a prenatal injection of the mitotic inhibitor methylazoxymethanol (MAM) into pregnant rats at embryonic day 15 (E15) or 17 (E17). The male offspring were tested when adult on a version of the radial-arm maze task that assesses spatial working memory with an extended delay, where performance is dependent, in part, on the hippocampal-prefrontal circuit. A major impairment of spatial learning was observed in E15 MAM rats. However, the E17 MAM rats did learn the rule but were impaired selectively in the 30-min delay-interposed task. Morphologically, the E15 MAM rats exhibited dramatic gross brain abnormalities, whereas the E17 MAM animals displayed aberrant cell migration in the hippocampus and a disrupted laminar pattern in the neocortex. These results suggest that late gestational MAM injection (E17) causes a cognitive impairment in a prefrontal cortex-hippocampus-dependent working memory task. This approach could provide a new developmental model of disorders associated with working memory deficits, such as schizophrenia.

Effect of long-term potentiation induction on gamma-band electroencephalograms in prefrontal cortex following stimulation of rat hippocampus in vivo.

We examined whether long-term potentiation (LTP) affects cortical gamma-band electroencephalograms (EEG) in the hippocampo-prefrontal cortex (PFC) pathway of anesthetized rats. The LTP induction increased the evoked PFC gamma-band EEG power (40-100 Hz) to 120-135% at 500-700 ms after test stimulation. A simple increment of stimulus intensity, instead of LTP induction, did not reveal this evoked increase. Neither LTP induction nor the intensity increment changed significantly the magnitude of an evoked decrease at around 100 ms or the spontaneous prestimulation gamma-band power. These results indicate that LTP in PFC specifically increases the evoked gamma-band EEG power, which may reflect a phasic mode of plastic neurotransmission through the hippocampo-PFC pathway in vivo.

Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo.

An intact mesocortical dopaminergic (DA) input to the prefrontal cortex (PFC) has been reported to be necessary for long-term potentiation (LTP) to occur at hippocampal-prefrontal cortex synapses. Here, we investigated the role of D1 and D2 receptors in this NMDA receptor-dependent LTP. Local infusion of the D1 agonist SKF81297 at an optimal dose induced a sustained enhancement of hippocampal-PFC LTP, whereas the D1 antagonist SCH23390 caused a dose-related impairment of its induction. The D1 agonist effect was mimicked by infusion of a low dose of the adenylyl cyclase activator forskolin, whereas LTP was severely attenuated with a protein kinase A inhibitor, Rp-cAMPS. To further assess the complex interplay between DA and NMDA receptors, changes in extracellular DA levels in the PFC were estimated during LTP, and a significant increase was observed immediately after tetanus. Taken together, these data suggest that D1 but not D2 receptors are crucial for the DA control of the NMDA receptor-mediated synaptic response on a specific excitatory input to the PFC. The interactions of these receptors may play a crucial role in the storage and transfer of hippocampal information in the PFC.

Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation.

The involvement of the hippocampus and the prefrontal cortex in cognitive processes and particularly in learning and memory has been known for a long time. However, the specific role of the projection which connects these two structures has remained elusive. The existence of a direct monosynaptic pathway from the ventral CA1 region of the hippocampus and subiculum to specific areas of the prefrontal cortex provides a useful model for conceptualizing the functional operations of hippocampal-prefrontal cortex communication in learning and memory. It is known now that hippocampal to prefrontal cortex synapses are modifiable synapses and can express different forms of plasticity, including long-term potentiation, long-term depression, and depotentiation. Here we review these findings and focus on recent studies that start to relate synaptic plasticity in the hippocampo-prefrontal cortex pathway to two specific aspects of learning and memory, i.e., the consolidation of information and working memory. The available evidence suggests that functional interactions between the hippocampus and prefrontal cortex in cognition and memory are more complex than previously anticipated, with the possibility for bidirectional regulation of synaptic strength as a function of the specific demands of tasks.

Excitotoxicity in neurological disorders--the glutamate paradox.

Beneficial effects of glutamate-receptor antagonists in models of neurological disorders are often used to support the notion that endogenous excitotoxicity (i.e. resulting from extracellular accumulation of endogenous glutamate) is a major contributor to neuronal death associated with these conditions. However, this interpretation conflicts with a number of robust and important experimental evidence. Here, emphasis is placed on two key elements: (i) very high extracellular levels of glutamate must be reached to initiate neuronal death, far above those measured in models of neurological disorders; and (ii) changes in extracellular glutamate as measured by microdialysis are not related to changes in the synaptic cleft, i.e. the compartment where neurotransmitter glutamate interacts with its receptors. It has become clear that the diversity and complexity of glutamate-mediated processes allow for a wide range of potential abnormalities (e.g. loss of selectivity of glutamate-operated ion channels, abnormal modulation of glutamate receptors). In addition, as neuronal death subsequent to ischemia and other insults is likely to result from multifactorial processes that may be inter-related, inhibition of glutamate-mediated synaptic transmission may be neuroprotective by increasing the resistance of neurons to other deleterious mechanisms (e.g. inadequate energy supply) that are not directly related to glutamatergic transmission.

Induction of stable long-term depression in vivo in the hippocampal-prefrontal cortex pathway.

We studied excitatory field potentials in the medial prefrontal cortex (mPFC, prelimbic area) to electrostimulation of the ventral hippocampus (CA1/subicular region) in the anaesthetized rat. Nine hundred stimulus trains (5 pulses at 250 Hz) applied at 1 Hz to the ventral hippocampus significantly and persistently depressed the amplitude and maximal slope ( approximately 55% for each index) of the prelimbic field potentials, but did not change the latency of the maximal slope or peak negativity. Twelve stimulus trains (50 pulses at 250 Hz) applied subsequently at 0.1 Hz restored the depression back to control level, and this reversible depression was maintained for at least 13 h. Cumulative depressive effects on the prelimbic field potential amplitude and maximal slope were observed upon addition of stimulus trains in the hippocampus. An important implication of the results is that the direct pathway from the hippocampus to the mPFC in the rat retains long-term depression (LTD) as a neuroplastic form in vivo. This form could cooperate with long-term potentiation (LTP) and such a bi-directional synaptic plasticity in the prefrontal cortex contributes to how cortical neural networks store information.

Long-term potentiation in the dentate gyrus is not linked to increased extracellular glutamate concentration.

Long-term potentiation (LTP) of excitatory transmission is a likely candidate for the encoding and storage of information in the mammalian brain. There is a general agreement that LTP involves an increase in synaptic strength, but the mechanisms underlying this persistent change are unclear and controversial. Synaptic efficacy may be enhanced because more transmitter glutamate is released or because postsynaptic responsiveness increases or both. The purpose of this study was to examine whether increased extracellular glutamate concentration was associated with the robust and well-characterized LTP that can be induced in the rat dentate gyrus. To favor the detection of any putative change in extracellular glutamate associated with LTP, our experimental strategy included the following features. 1) Two separate series of experiments were carried out with animals under pentobarbital or urethan anesthesia; 2) changes in extracellular concentration of glutamate were monitored continuously by microdialysis coupled to enzyme amperometry; and 3) dialysate glutamate levels and changes in the slope of excitatory postsynaptic potential evoked by activation of the perforant path were recorded precisely at the same site. Tetanic stimulation of the perforant path increased persistently test-evoked responses in the dentate gyrus (by 19 and 14% in barbiturate and urethan group, respectively), but there was no glutamate change either during or after LTP induction and no indication of increased glutamate efflux when low-frequency stimulation was applied. The results do not rule out a possible contribution of enhanced glutamate exocytosis to LTP induction and/or maintenance because such a presynaptic change may not be detectable extracellularly. However, our findings and other data supporting the notion that neurotransmitter glutamate may hardly leak out of the synaptic cleft conflict with the hypothesis that LTP could also involve a broad synaptic spillover of glutamate.

Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation.

The prefrontal cortex receives dopaminergic inputs from the ventral tegmental area and excitatory inputs from the hippocampus. Both afferent pathways target in close proximity dendritic spines of pyramidal cells in layer V-VI of the prefrontal cortex. In view of the prominent role of dopamine in cognitive functions we examined the effects of ventral tegmental area stimulation on the induction of long-term potentiation in the hippocampal-prefrontal cortex pathway of anesthetized rats. Stimulation of the ventral tegmental area at a frequency known to evoke dopamine overflow in the prefrontal cortex produces a long-lasting enhancement of the magnitude of the hippocampal-prefrontal cortex long-term potentiation. The role of dopamine was further examined by investigating the effects of prefrontocortical dopamine depletion induced by an electrolytic ventral tegmental area lesion. A significant correlation (r = 0.8; P < 0.001; n = 14) was obtained between cortical dopamine levels and cortical long-term potentiation amplitude, a depletion of more than 50% of cortical levels corresponding to a dramatic decrease in hippocampal-prefrontal cortex long-term potentiation. However, a recovery to normal long-term potentiation was observed 1 h after tetanic stimulation. In contrast to the effects on long-term potentiation, ventral tegmental area stimulation, when applied at low or high frequency, decreases the amplitude of the hippocampal-prefrontal cortex postsynaptic synaptic response. The present study demonstrates the importance of the integrity of the mesocortical dopaminergic system for long-term potentiation to occur in the hippocampal-prefrontal cortex pathway and suggests a frequency-dependent effect of dopamine on hippocampal-prefrontal cortex transmission.

Rapid increase in PKA activity during long-term potentiation in the hippocampal afferent fibre system to the prefrontal cortex in vivo.

The purpose of the present study was to examine whether cAMP-dependent protein kinase (PKA) was implicated in the process of long-term potentiation (LTP) in the hippocampal afferent fibre system to the prefrontal cortex in vivo. Using a biochemical approach, we measured PKA activity at different times after induction of LTP. We show that there is an NMDA receptor-dependent increase in PKA activity in the prefrontal cortex, only at five minutes after LTP induction. These data demonstrate a role of PKA in the induction and not the expression of cortical LTP and suggest that if PKA is involved in the late phase of LTP, it does not appear to be a persistent activation.