Repeated Anodal Transcranial Direct Current Stimulation (RA-tDCS) over the Left Frontal Lobe Increases Bilateral Hippocampal Cell Proliferation in Young Adult but Not Middle-Aged Female Mice.

Repeated anodal transcranial direct current stimulation (RA-tDCS) is a neuromodulatory technique consisting of stimulating the cerebral cortex with a weak electric anodal current in a non-invasive manner. RA-tDCS over the dorsolateral prefrontal cortex has antidepressant-like properties and improves memory both in humans and laboratory animals. However, the mechanisms of action of RA-tDCS remain poorly understood. Since adult hippocampal neurogenesis is thought to be involved in the pathophysiology of depression and memory functioning, the purpose of this work was to evaluate the impact of RA-tDCS on hippocampal neurogenesis levels in mice. RA-tDCS was applied for 20 min per day for five consecutive days over the left frontal cortex of young adult (2-month-old, high basal level of neurogenesis) and middle-aged (10-month-old, low basal level of neurogenesis) female mice. Mice received three intraperitoneal injections of bromodeoxyuridine (BrdU) on the final day of RA-tDCS. The brains were collected either 1 day or 3 weeks after the BrdU injections to quantify cell proliferation and cell survival, respectively. RA-tDCS increased hippocampal cell proliferation in young adult female mice, preferentially (but not exclusively) in the dorsal part of the dentate gyrus. However, the number of cells that survived after 3 weeks was the same in both the Sham and the tDCS groups. This was due to a lower survival rate in the tDCS group, which suppressed the beneficial effects of tDCS on cell proliferation. No modulation of cell proliferation or survival was observed in middle-aged animals. Our RA-tDCS protocol may, therefore, influence the behavior of naïve female mice, as we previously described, but its effect on the hippocampus is only transient in young adult animals. Future studies using animal models for depression in male and female mice should provide further insights into RA-tDCS detailed age- and sex-dependent effects on hippocampal neurogenesis.

Beneficial effects of prolonged 2-phenylethyl alcohol inhalation on chronic distress-induced anxio-depressive-like phenotype in female mice.

Chronic distress-induced hypothalamic-pituitary-adrenal axis deregulations have been associated with the development of neuropsychiatric disorders such as anxiety and depression. Currently available drugs treating such pathological conditions have limited efficacy and diverse side effects, revealing the need of new safer strategies. Aromatic plant-based compounds are largely used in herbal medicine due to their therapeutic properties on mood, physiology, and general well-being. The purpose of this study was to investigate the effects of 2-phenylethyl alcohol (PEA), one of the pharmacologically active constituents of rose essential oil, on chronic corticosterone (CORT)-induced behavioral and neurobiological changes in female mice. Animals followed a prolonged PEA inhalation exposure (30 min per day) for 15 consecutive days prior to behavioral evaluation with open-field, forced swim and novelty-suppressed feeding tests. CORT treatment induced an anxio-depressive-like phenotype, evidenced by a reduced locomotor activity in the open-field, and an increased latency to feed in the novelty-suppressed feeding paradigms. To elucidate the neural correlates of our behavioral results, immunohistochemistry was further performed to provide a global map of neural activity based on cerebral cFos expression. The altered feeding behavior was accompanied by a significant decrease in the number of cFos-positive cells in the olfactory bulb, and altered functional brain connectivity as shown by cross-correlation-based network analysis. CORT-induced behavioral and neurobiological alterations were reversed by prolonged PEA inhalation, suggesting a therapeutic action that allows regulating the activity of neural circuits involved in sensory, emotional and feeding behaviors. These findings might contribute to better understand the therapeutic potential of PEA on anxio-depressive symptoms.

Chronic Distress in Male Mice Impairs Motivation Compromising Both Effort and Reward Processing With Altered Anterior Insular Cortex and Basolateral Amygdala Neural Activation.

In humans and mammals, effort-based decision-making for monetary or food rewards paradigms contributes to the study of adaptive goal-directed behaviours acquired through reinforcement learning. Chronic distress modelled by repeated exposure to glucocorticoids in rodents induces suboptimal decision-making under uncertainty by impinging on instrumental acquisition and prompting negative valence behaviours. In order to further disentangle the motivational tenets of adaptive decision-making, this study addressed the consequences of enduring distress on relevant effort and reward-processing dimensions. Experimentally, appetitive and consummatory components of motivation were evaluated in adult C57BL/6JRj male mice experiencing chronic distress induced by oral corticosterone (CORT), using multiple complementary discrete behavioural tests. Behavioural data (from novelty suppressed feeding, operant effort-based choice, free feeding, and sucrose preference tasks) collectively show that behavioural initiation, effort allocation, and hedonic appreciation and valuation are altered in mice exposed to several weeks of oral CORT treatment. Additionally, data analysis from FosB immunohistochemical processing of postmortem brain samples highlights CORT-dependent dampening of neural activation in the anterior insular cortex (aIC) and basolateral amygdala (BLA), key telencephalic brain regions involved in appetitive and consummatory motivational processing. Combined, these results suggest that chronic distress-induced irregular aIC and BLA neural activations with reduced effort production and attenuated reward value processing during reinforcement-based instrumental learning could result in maladaptive decision-making under uncertainty. The current study further illustrates how effort and reward processing contribute to adjust the motivational threshold triggering goal-directed behaviours in versatile environments.

Chronic exposure to glucocorticoids induces suboptimal decision-making in mice.

Anxio-depressive symptoms as well as severe cognitive dysfunction including aberrant decision-making (DM) are documented in neuropsychiatric patients with hypercortisolaemia. Yet, the influence of the hypothalamo-pituitary-adrenal (HPA) axis on DM processes remains poorly understood. As a tractable mean to approach this human condition, adult male C57BL/6JRj mice were chronically treated with corticosterone (CORT) prior to behavioural, physiological and neurobiological evaluation. The behavioural data indicate that chronic CORT delays the acquisition of contingencies required to orient responding towards optimal DM performance in a mouse Gambling Task (mGT). Specifically, CORT-treated animals show a longer exploration and a delayed onset of the optimal DM performance. Remarkably, the proportion of individuals performing suboptimally in the mGT is increased in the CORT condition. This variability seems to be better accounted for by variations in sensitivity to negative rather than to positive outcome. Besides, CORT-treated animals perform worse than control animals in a spatial working memory (WM) paradigm and in a motor learning task. Finally, Western blotting neurobiological analyses show that chronic CORT downregulates glucocorticoid receptor expression in the medial Prefrontal Cortex (mPFC). Besides, corticotropin-releasing factor signalling in the mPFC of CORT individuals negatively correlates with their DM performance. Collectively, this study describes how chronic exposure to glucocorticoids induces suboptimal DM under uncertainty in a mGT, hampers WM and motor learning processes, thus affecting specific emotional, motor, cognitive and neurobiological endophenotypic dimensions relevant for precision medicine in biological psychiatry.

A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior.

The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.

Modelling decision-making under uncertainty: A direct comparison study between human and mouse gambling data.

Decision-making is a conserved evolutionary process enabling us to choose one option among several alternatives, and relies on reward and cognitive control systems. The Iowa Gambling Task allows the assessment of human decision-making under uncertainty by presenting four card decks with various cost-benefit probabilities. Participants seek to maximise their monetary gain by developing long-term optimal-choice strategies. Animal versions have been adapted with nutritional rewards, but interspecies data comparisons are scarce. Our study directly compares the non-pathological decision-making performance between humans and wild-type C57BL/6 mice. Human participants completed an electronic Iowa Gambling Task version, while mice a maze-based adaptation with four arms baited in a probabilistic way. Our data shows closely matching performance between both species with similar patterns of choice behaviours. However, mice showed a faster learning rate than humans. Moreover, both populations were clustered into good, intermediate and poor decision-making categories with similar proportions. Remarkably, mice characterised as good decision-makers behaved the same as humans of the same category, but slight differences among species are evident for the other two subpopulations. Overall, our direct comparative study confirms the good face validity of the rodent gambling task. Extended behavioural characterisation and pathological animal models should help strengthen its construct validity and disentangle the determinants in animals and humans decision-making.

Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning.

Associative learning is thought to involve different forms of activity-dependent synaptic plasticity. Although previous studies have mostly focused on learning-related changes occurring at excitatory glutamatergic synapses, we found that associative learning, such as fear conditioning, also entails long-lasting functional and structural plasticity of GABAergic synapses onto pyramidal neurons of the murine basal amygdala. Fear conditioning-mediated structural remodeling of GABAergic synapses was associated with a change in mIPSC kinetics and an increase in the fraction of synaptic benzodiazepine-sensitive (BZD) GABAA receptors containing the α2 subunit without altering the intrasynaptic distribution and overall amount of BZD-GABAA receptors. These structural and functional synaptic changes were partly reversed by extinction training. These findings provide evidence that associative learning, such as Pavlovian fear conditioning and extinction, sculpts inhibitory synapses to regulate inhibition of active neuronal networks, a process that may tune amygdala circuit responses to threats.

Fatty Acid Lingual Application Activates Gustatory and Reward Brain Circuits in the Mouse.

The origin of spontaneous preference for dietary lipids in humans and rodents is debated, though recent compelling evidence has shown the existence of fat taste that might be considered a sixth taste quality. We investigated the implication of gustatory and reward brain circuits, triggered by linoleic acid (LA), a long-chain fatty acid. The LA was applied onto the circumvallate papillae for 30 min in conscious C57BL/6J mice, and neuronal activation was assessed using c-Fos immunohistochemistry. By using real-time reverse transcription polymerase chain reaction (RT-qPCR), we also studied the expression of mRNA encoding brain-derived neurotrophic factor (BDNF), Zif-268, and Glut-1 in some brain areas of these animals. LA induced a significant increase in c-Fos expression in the nucleus of solitary tract (NST), parabrachial nucleus (PBN), and ventroposterior medialis parvocellularis (VPMPC) of the thalamus, which are the regions known to be activated by gustatory signals. LA also triggered c-Fos expression in the central amygdala and ventral tegmental area (VTA), involved in food reward, in conjunction with emotional traits. Interestingly, we noticed a high expression of BDNF, Zif-268, and Glut-1 mRNA in the arcuate nucleus (Arc) and hippocampus (Hipp), where neuronal activation leads to memory formation. Our study demonstrates that oral lipid taste perception might trigger the activation of canonical gustatory and reward pathways.

Parasubthalamic and calbindin nuclei in the posterior lateral hypothalamus are the major hypothalamic targets for projections from the central and anterior basomedial nuclei of the amygdala.

The parasubthalamic nucleus (PSTN) and the ventrally adjacent calbindin nucleus (CbN) form a nuclear complex in the posterior lateral hypothalamic area (LHA), recently characterized as connected with the central nucleus of the amygdala (CEA). The aim of the present work is to analyze in detail the projections from the amygdala into the PSTN/CbN, also focusing on pathways into the LHA. After fluorogold injections into the PSTN/CbN, the medial part of the CEA (CEAm) appears to be the main supplier of projections from the CEA. Other amygdalar nuclei contribute to the innervation of the PSTN/CbN complex, including the anterior part of the basomedial nucleus (BMAa). Injections of the anterograde tracer, Phaseolus vulgaris leucoagglutinin (PHAL), into the CEAm and BMAa revealed that projections from the CEAm follow two pathways into the LHA: a dorsal pathway formed by axons that also innervate the paraventricular hypothalamic nucleus, the anterior perifornical LHA and the PSTN, and a ventral pathway that runs laterally adjacent to the ventrolateral hypothalamic tract (vlt) and ends in the CbN. By contrast, the BMAa and other telencephalic structures, such as the fundus striatum project to the CbN via the ventral pathway. Confirming the microscopic observation, a semi-quantitative analysis of the density of these projections showed that the PSTN and the CbN are the major hypothalamic targets for the projections from the CEAm and the BMAa, respectively. PSTN and CbN receive these projections through distinct dorsal and ventral routes in the LHA. The ventral pathway forms a differentiated tract, named here the ventrolateral amygdalo-hypothalamic tract (vlah), that is distinct from, but runs adjacent to, the vlt. Both the vlt and the vlah had been previously described as forming an olfactory path into the LHA. These results help to better characterize the CbN within the PSTN/CbN complex and are discussed in terms of the functional organization of the network involving the PSTN and the CbN as well as the CEA and the BMAa.

A premammillary lateral hypothalamic nuclear complex responds to hedonic but not aversive tastes in the male rat.

The lateral hypothalamic area (LHA) has two major roles: arousal/waking and food intake controls. Here, it is shown that a premammillary part of the LHA is neurochemically and cytoarchitectonically distinct from the tuberal LHA in male rats. This part contains nuclear masses, namely the parasubthalamic nucleus and the calbindin nucleus, involved in pathways that predict its participation in the control of food intake. Analyzing c-Fos expression in experiments related to feeding behavior, this region responded specifically to the ingestion of palatable nutriments.

Transcranial direct current stimulation for memory enhancement: from clinical research to animal models.

There is a growing demand for new brain-enhancing technologies to improve mental performance, both for patients with cognitive disorders and for healthy individuals. Transcranial direct current stimulation (tDCS) is a non-invasive, painless, and easy to use neuromodulatory technique that can improve performance on a variety of cognitive tasks in humans despite its exact mode of action remains unclear. We have conducted a mini-review of the literature to first briefly summarize the growing amount of data from clinical trials assessing the efficacy of tDCS, focusing exclusively on learning and memory performances in healthy human subjects and in patients with depression, schizophrenia, and other neurological disorders. We then discuss these findings in the context of the strikingly few studies resulting from animal research. Finally, we highlight future directions and limitations in this field and emphasize the need to develop translational studies to better understand how tDCS improves memory, a necessary condition before it can be used as a therapeutic tool.

A new neuronal target for ß-amyloid peptide in the rat hippocampus.

In Alzheimer's disease, amyloid beta peptide (Aß) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aß induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aß treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aß deposits. We observed that in Aß-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aß can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aß, one of the main agents of dementia in Alzheimer's disease.