The Dopaminergic Cells in the Median Raphe Region Regulate Social Behavior in Male Mice.

According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response.

Lateral septum as a possible regulatory center of maternal behaviors.

The lateral septum (LS) is involved in controlling anxiety, aggression, feeding, and other motivated behaviors. Lesion studies have also implicated the LS in various forms of caring behaviors. Recently, novel experimental tools have provided a more detailed insight into the function of the LS, including the specific role of distinct cell types and their neuronal connections in behavioral regulations, in which the LS participates. This article discusses the regulation of different types of maternal behavioral alterations using the distributions of established maternal hormones such as prolactin, estrogens, and the neuropeptide oxytocin. It also considers the distribution of neurons activated in mothers in response to pups and other maternal activities, as well as gene expressional alterations in the maternal LS. Finally, this paper proposes further research directions to keep up with the rapidly developing knowledge on maternal behavioral control in other maternal brain regions.

Sleep and local field potential effect of the D2 receptor agonist bromocriptine during the estrus cycle and postpartum period in female rats.

BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.

Sleep- and sleep deprivation-related changes of vertex auditory evoked potentials during the estrus cycle in female rats.

The estrus cycle in female rodents has been shown to affect a variety of physiological functions. However, little is known about its presumably thorough effect on auditory processing during the sleep-wake cycle and sleep deprivation. Vertex auditory evoked potentials (vAEPs) were evoked by single click tone stimulation and recorded during different stages of the estrus cycle and sleep deprivation performed in metestrus and proestrus in female rats. vAEPs showed a strong sleep-dependency, with the largest amplitudes present during slow wave sleep while the smallest ones during wakefulness. Higher amplitudes and longer latencies were seen in the light phase during all vigilance stages. The largest amplitudes were found during proestrus (light phase) while the shortest latencies were seen during estrus (dark phase) compared to the 2nd day diestrus baseline. High-amplitude responses without latency changes were also seen during metestrus with increased homeostatic sleep drive. More intense and faster processing of auditory information during proestrus and estrus suggesting a more effective perception of relevant environmental cues presumably in preparation for sexual receptivity. A 4-h sleep deprivation resulted in more pronounced sleep recovery in metestrus compared to proestrus without difference in delta power replacement suggesting a better tolerance of sleep deprivation in proestrus. Sleep deprivation decreased neuronal excitability and responsiveness in a similar manner both during metestrus and proestrus, suggesting that the negative consequences of sleep deprivation on auditory processing may have a limited correlation with the estrus cycle stage.

Microglia depletion prevents lactation by inhibition of prolactin secretion.

Microglial cells were eliminated from the brain with sustained 3-4 weeks long inhibition of colony stimulating factor 1 receptor by Pexidartinib 3397 (PLX3397). The prepartum treated mice mothers did not feed their pups after parturition. The pups of mothers treated orally only in the postpartum period starting immediately after parturition showed reduced body weight by 15.5 ± 0.22 postnatal days as the treatment progressed without the mothers showing altered caring behaviors. The apparent weight gain of foster pups during a suckling bout was reduced in mother mice fed by PLX3397-containing diet and also in rat dams following sustained intracerebroventricular infusion of PLX3397 in a separate experiment suggesting that lactation was affected by the reduced number of microglia. Prolactin secretion and signaling were markedly reduced in PLX3397-treated mothers. The results suggest that microglial cells are required for prolactin secretion and lactation whereas maternal motivation may not be directly affected by microglia.

The increase in the number of amylin neurons in the medial preoptic area throughout the lactational period and its relationship with melanin-concentrating hormone.

The amylin and the melanin-concentrating hormone [MCH] are two peptides related to energetic homeostasis. During lactation, it is possible to locate neurons expressing these peptides in the preoptic area of rat dams. In addition, it was demonstrated that the number of MCH neurons in this region is modulated by litter size. Taken together, the aims of this work were (1) to verify the time course of amylin immunoreactivity during lactation; (2) to verify whether litter size modulates the number of amylin-ir neurons (3) to verify whether there is colocalization between the amylin-ir and MCH-ir neurons. Our results show that (1) there is an increase in the number of amylin-ir neurons during lactation, which reaches a peak at postpartum day 19 and drastically reduces after weaning; (2) there is no correlation between litter size and the number of amylin-ir neurons; and (3) there is minimal overlap between amylin-ir and MCH-ir neurons.

Anti-glutamatergic Effects of Three Lignan Compounds: Arctigenin, Matairesinol and Trachelogenin - An ex vivo Study on Rat Brain Slices.

Arctigenin is a bioactive dibenzylbutyrolactone-type lignan exhibiting various pharmacological activities. The neuroprotective effects of arctigenin were demonstrated to be mediated via inhibition of AMPA and KA type glutamate receptors in the somatosensory cortex of the rat brain. The aim of this study was to compare the effects of arctigenin with matairesinol and trachelogenin on synaptic activity in ex vivo rat brain slices. Arctigenin, matairesinol and trachelogenin were isolated from Arctium lappa, Centaurea scabiosa and Cirsium arvense, respectively, and applied on brain slices via perfusion medium at the concentration range of 0.5 - 40 µM. The effects of the lignans were examined in the CA1 hippocampus and the somatosensory cortex by recording electrically evoked field potentials. Arctigenin and trachelogenin caused a significant dose-dependent decrease in the amplitude of hippocampal population spikes (POPS) and the slope of excitatory postsynaptic potentials (EPSPs), whereas matairesinol (1 µM and 10 µM) decreased EPSP slope but had no effect on POPS amplitude. Trachelogenin effect (0.5 µM, 10 µM, 20 µM) was comparable to arctigenin (1 µM, 20 µM, 40 µM) (p > 0.05). In the neocortex, arctigenin (10 µM, 20 µM) and trachelogenin (10 µM) significantly decreased the amplitude of evoked potential early component, while matairesinol (1 µM and 10 µM) had no significant effect (p > 0.05). The results suggest that trachelogenin and arctigenin act via inhibition of AMPA and KA receptors in the brain and trachelogenin has a higher potency than arctigenin. Thus, trachelogenin and arctigenin could serve as lead compounds in the development of neuroprotective drugs.

Elevated Glucagon-like Peptide-1 Receptor Level in the Paraventricular Hypothalamic Nucleus of Type 2 Diabetes Mellitus Patients.

Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have been approved for the treatment of type 2 diabetes mellitus (T2DM); however, the brain actions of these drugs are not properly established. We used post mortem microdissected human hypothalamic samples for RT-qPCR and Western blotting. For in situ hybridization histochemistry and immunolabelling, parallel cryosections were prepared from the hypothalamus. We developed in situ hybridization probes for human GLP-1R and oxytocin. In addition, GLP-1 and oxytocin were visualized by immunohistochemistry. Radioactive in situ hybridization histochemistry revealed abundant GLP-1R labelling in the human paraventricular hypothalamic nucleus (PVN), particularly in its magnocellular subdivision (PVNmc). Quantitative analysis of the mRNA signal demonstrated increased GLP-1R expression in the PVNmc in post mortem hypothalamic samples from T2DM subjects as compared to controls, while there was no difference in the expression level of GLP-1R in the other subdivisions of the PVN, the hypothalamic dorsomedial and infundibular nuclei. Our results in the PVN were confirmed by RT-qPCR. Furthermore, we demonstrated by Western blot technique that the GLP-1R protein level was also elevated in the PVN of T2DM patients. GLP-1 fibre terminals were also observed in the PVNmc closely apposing oxytocin neurons using immunohistochemistry. The data suggest that GLP-1 activates GLP-1Rs in the PVNmc and that GLP-1R is elevated in T2DM patients, which may be related to the dysregulation of feeding behaviour and glucose homeostasis in T2DM.

Effects of dibenzylbutyrolactone lignans arctigenin and trachelogenin on the motility of isolated rat ileum.

Dibenzylbutyrolactone-type lignans are phenolic compounds of medical importance. The purpose of the study was to determine the effects of two such lignans, arctigenin and trachelogenin on the motility of isolated rat ileum and obtain indications on their mechanism of action. They were isolated from Arctium lappa and Cirsium arvense, respectively, which have been used traditionally to treat gastrointestinal disorders. 1-1.5 cm long segments of distal ileum were obtained from adult male Wistar rats. The intestinal segments were suspended vertically in a well-aerated organ-bath according to Magnus mounting method. The intestinal motility was monitored for 30 min before treatment to obtain the baseline, followed by treatment with 1 µM, 10 µM, 20 µM and 40 µM concentrations of arctigenin and 0.5 µM, 1 µM, 10 µM and 20 µM of trachelogenin concentrations. The amplitude, tone, and period of spontaneous contractions were measured after 15 and 30 min of treatment. To investigate their mechanism of action, cholinergic, glutamatergic, adrenergic antagonists and compounds inhibiting nitric oxide synthase and L-type calcium channels were also tested. Arctigenin and trachelogenin decreased the frequency of contractions in a dose-dependent manner. At the concentration of 20 µM and 40 µM of trachelogenin and arctigenin, respectively, there was a marked alteration in spontaneous contraction pattern with an observable increase in the period time. This activity was comparable to 0.5 µM nifedipine (L-type calcium channel blocker) treatment. Our results demonstrate relaxant effect of arctigenin and trachelogenin on the ileum motility that may be mediated by L-type calcium ion channel blockade.

A thalamo-preoptic pathway promotes social grooming in rodents.

Social touch is an essential component of communication. Little is known about the underlying pathways and mechanisms. Here, we discovered a novel neuronal pathway from the posterior intralaminar thalamic nucleus (PIL) to the medial preoptic area (MPOA) involved in the control of social grooming. We found that the neurons in the PIL and MPOA were naturally activated by physical contact between female rats and also by the chemogenetic stimulation of PIL neurons. The activity-dependent tagging of PIL neurons was performed in rats experiencing physical social contact. The chemogenetic activation of these neurons increased social grooming between familiar rats, as did the selective activation of the PIL-MPOA pathway. Neurons projecting from the PIL to the MPOA express the neuropeptide parathyroid hormone 2 (PTH2), and the central infusion of its receptor antagonist diminished social grooming. Finally, we showed a similarity in the anatomical organization of the PIL and the distribution of the PTH2 receptor in the MPOA between the rat and human brain. We propose that the discovered neuronal pathway facilitates physical contact with conspecifics.

Transcriptome Profiling of the Dorsomedial Prefrontal Cortex in Suicide Victims.

The default mode network (DMN) plays an outstanding role in psychiatric disorders. Still, gene expressional changes in its major component, the dorsomedial prefrontal cortex (DMPFC), have not been characterized. We used RNA sequencing in postmortem DMPFC samples to investigate suicide victims compared to control subjects. 1400 genes differed using log2FC > ±1 and adjusted p-value < 0.05 criteria between groups. Genes associated with depressive disorder, schizophrenia and impaired cognition were strongly overexpressed in top differentially expressed genes. Protein−protein interaction and co-expressional networks coupled with gene set enrichment analysis revealed that pathways related to cytokine receptor signaling were enriched in downregulated, while glutamatergic synaptic signaling upregulated genes in suicidal individuals. A validated differentially expressed gene, which is known to be associated with mGluR5, was the N-terminal EF-hand calcium-binding protein 2 (NECAB2). In situ hybridization histochemistry and immunohistochemistry proved that NECAB2 is expressed in two different types of inhibitory neurons located in layers II-IV and VI, respectively. Our results imply extensive gene expressional alterations in the DMPFC related to suicidal behavior. Some of these genes may contribute to the altered mental state and behavior of suicide victims.

Behavioural actions of tuberoinfundibular peptide 39 (parathyroid hormone 2).

Tuberoinfundibular peptide of 39 residues (TIP39) acts via its endogenous class B G-protein coupled receptorthe parathyroid hormone 2 receptor (PTH2R). Hence, it is also known as parathyroid hormone 2. The peptide is expressed in the brain by a small number of neurons with a highly restricted distribution, which in turn project to a large number of brain regions that contain PTH2R. This peptide neuromodulator system has been extensively investigated over the past 20 years including its behavioural actions, such as its role in the control of nociception, fear and fear incubation, anxiety and depression-like behaviours, and maternal and social behaviours. It also influences thermoregulation and potentially auditory responses. TIP39 probably exerts direct effect on the neuronal networks controlling these behaviours based on the localization of PTH2R and local TIP39 actions. In addition, TIP39 also affects the secretion of several hypothalamic hormones providing the basis for indirect behavioural actions. Recently developed experimental tools have stimulated further behavioural investigations, and novel results obtained are discussed in this review.

Tracking Highly Similar Rat Instances under Heavy Occlusions: An Unsupervised Deep Generative Pipeline.

Identity tracking and instance segmentation are crucial in several areas of biological research. Behavior analysis of individuals in groups of similar animals is a task that emerges frequently in agriculture or pharmaceutical studies, among others. Automated annotation of many hours of surveillance videos can facilitate a large number of biological studies/experiments, which otherwise would not be feasible. Solutions based on machine learning generally perform well in tracking and instance segmentation; however, in the case of identical, unmarked instances (e.g., white rats or mice), even state-of-the-art approaches can frequently fail. We propose a pipeline of deep generative models for identity tracking and instance segmentation of highly similar instances, which, in contrast to most region-based approaches, exploits edge information and consequently helps to resolve ambiguity in heavily occluded cases. Our method is trained by synthetic data generation techniques, not requiring prior human annotation. We show that our approach greatly outperforms other state-of-the-art unsupervised methods in identity tracking and instance segmentation of unmarked rats in real-world laboratory video recordings.

Transcriptomics of Parental Care in the Hypothalamic-Septal Region of Female Zebra Finch Brain.

(1) Background: The objective of this study was to uncover genomic causes of parental care. Since birds do not lactate and, therefore, do not show the gene expressional changes required for lactation, we investigate gene expression associated with parenting in caring and non-caring females in an avian species, the small passerine bird zebra finch (Taeniopygia guttata). Here, we compare expression patterns in the hypothalamic-septal region since, previously, we showed that this area is activated in parenting females. (2) Methods: Transcriptome sequencing was first applied in a dissected part of the zebra finch brain related to taking care of the nestlings as compared to a control group of social pairs without nestlings. (3) Results: We found genes differentially expressed between caring and non-caring females. When introducing a log2fold change threshold of 1.5, 13 annotated genes were significantly upregulated in breeding pairs, while 39 annotated genes were downregulated. Significant enrichments of dopamine and acetylcholine biosynthetic processes were identified among upregulated pathways, while pro-opiomelanocortin and thyroid hormone pathways were downregulated, suggesting the importance of these systems in parental care. Network analysis further suggested neuro-immunological changes in mothers. (4) Conclusions: The results confirm the roles of several hypothesized major pathways in parental care, whereas novel pathways are also proposed.

Sex-specific parenting and depression evoked by preoptic inhibitory neurons.

The role of preoptic GABAergic inhibitory neurons was addressed in parenting, anxiety and depression. Pup exposure and forced swimming resulted in similar c-Fos activation pattern in neurons expressing vesicular GABA transporter in the preoptic area with generally stronger labeling and different distributional pattern in females than in males. Chemogenetic stimulation of preoptic GABAergic cells resulted in elevated maternal motivation and caring behavior in females and mothers but aggression toward pups in males. Behavioral effects were the opposite following inhibition of preoptic GABAergic neurons suggesting their physiological relevance. In addition, increased anxiety-like and depression-like behaviors were found following chemogenetic stimulation of the same neurons in females, whereas previous pup exposure increased only anxiety-like behavior suggesting that not the pups, but overstimulation of the cells can lead to depression-like behavior. A sexually dimorphic projection pattern of preoptic GABAergic neurons was also identified, which could mediate sex-dependent parenting and associated emotional behaviors.

Zearalenone alters the excitability of rat neuronal networks after acute in vitro exposure.

Zearalenone (ZEA) is a mycotoxin produced by Fusarium species, detectable in various cereals and processed food products worldwide. ZEA displays a significant estrogenic activity, thus its main health risk is the interference with sexual maturation and reproduction processes. However, in addition to being key hormonal regulators of reproductive function, estrogenic compounds have a widespread role in brain, as neurotrophic and neuroprotective factors, and they may influence the activity of several brain areas not directly linked to reproduction, as well. Therefore, in the present study, acute effects of ZEA were studied on certain neuronal functions in rats. Experiments were performed on rat brain slices or live rats. Slices were incubated in ZEA-containing (10-100 µM) solution for 30 min. Electrically evoked and spontaneous field potentials were studied in the neocortex and in the hippocampus. At higher concentrations, ZEA incubation of the slices altered excitability and the pattern of epileptiform activity in neocortex and inhibited the development of LTP in hippocampus. For the verification of these in vitro results, in vivo electrophysiological and immunohistochemical investigations were also performed. ZEA was administered systemically (5 mg/kg, i.p.) to male rats and somatosensory evoked potentials and neuronal activation studied by c-fos expression were analyzed. No neuronal activation could be demonstrated in the hippocampus within 2 h of the injection. In the somatosensory cortex, ZEA did not change in vivo evoked potential parameters, but the activation of a small neuronal population could be demonstrated with the c-fos technique in this brain area. This result could be associated with the ZEA-induced alteration of epileptiform activity observed in vitro. Altogether, the toxin altered the excitability and plasticity of neuronal networks after direct treatment in slices, but the effects were less prominent on the given brain areas after systemic treatment in vivo. A probable explanation for the partial lack of in vivo effects may be that after a single injection, ZEA did not cross the blood-brain barrier at sufficient rate to allow the build-up of comparable concentrations in the investigated brain areas. However, in case of compromised blood-brain barrier functions or long-term repeated exposure, alterations in cortical and hippocampal functions cannot be ruled out.

Transcriptome Sequencing in the Preoptic Region of Rat Dams Reveals a Role of Androgen Receptor in the Control of Maternal Behavior.

(1) Background: Preoptic region of hypothalamus is responsible to control maternal behavior, which was hypothesized to be associated with gene expressional changes. (2) Methods: Transcriptome sequencing was first applied in the preoptic region of rat dams in comparison to a control group of mothers whose pups were taken away immediately after parturition and did not exhibit caring behavior 10 days later. (3) Results: Differentially expressed genes were found and validated by quantitative RT-PCR, among them NACHT and WD repeat domain containing 1 (Nwd1) is known to control androgen receptor (AR) protein levels. The distribution of Nwd1 mRNA and AR was similar in the preoptic area. Therefore, we focused on this steroid hormone receptor and found its reduced protein level in rat dams. To establish the function of AR in maternal behavior, its antagonist was administered intracerebroventricularly into mother rats and increased pup-directed behavior of the animals. (4) Conclusions: AR levels are suppressed in the preoptic area of mothers possibly mediated by altered Nwd1 expression in order to allow sustained high-level care for the pups. Thus, our study first implicated the AR in the control of maternal behaviors.

Secretion and Function of Pituitary Prolactin in Evolutionary Perspective.

The hypothalamo-pituitary system developed in early vertebrates. Prolactin is an ancient vertebrate hormone released from the pituitary that exerts particularly diverse functions. The purpose of the review is to take a comparative approach in the description of prolactin, its secretion from pituitary lactotrophs, and hormonal functions. Since the reproductive and osmoregulatory roles of prolactin are best established in a variety of species, these functions are the primary subjects of discussion. Different types of prolactin and prolactin receptors developed during vertebrate evolution, which will be described in this review. The signal transduction of prolactin receptors is well conserved among vertebrates enabling us to describe the whole subphylum. Then, the review focuses on the regulation of prolactin release in mammals as we have the most knowledge on this class of vertebrates. Prolactin secretion in response to different reproductive stimuli, such as estrogen-induced release, mating, pregnancy and suckling is detailed. Reproduction in birds is different from that in mammals in several aspects. Prolactin is released during incubation in avian species whose regulation and functional significance are discussed. Little information is available on prolactin in reptiles and amphibians; therefore, they are mentioned only in specific cases to explain certain evolutionary aspects. In turn, the osmoregulatory function of prolactin is well established in fish. The different types of pituitary prolactin in fish play particularly important roles in the adaptation of eutherian species to fresh water environments. To achieve this function, prolactin is released from lactotrophs in hyposmolarity, as they are directly osmosensitive in fish. In turn, the released prolactin acts on branchial epithelia, especially ionocytes of the gill to retain salt and excrete water. This review will highlight the points where comparative data give new ideas or suggest new approaches for investigation in other taxa.

Short-term neuronal effects of fumonisin B1 on neuronal activity in rodents.

Fumonisin B1 (FB1) is a mycotoxin produced by microscopic fungi (mostly Fusarium species), which may infect our major crops. The toxin inhibits the development of these plants and may also have harmful effects on animals and humans consuming the infected crops. FB1 inhibits sphingolipid biosynthesis which leads to altered membrane characteristics and consequently, altered cellular functions. There are some indications that the toxin has inhibitory effects on neuronal activity in case of repeated consumption, presumably due to sphingolipid depletion. However, according to new literature data, FB1 may have acute excitatory neural effects, too, via different mechanisms of action. Therefore, in the present study, we addressed the neuronal network effects of FB1 following acute treatment, using different electrophysiological techniques in vitro and in vivo. Acute treatments with FB1 (10-100 µM) were carried out on brain slices, tissue cultures and live animals. After direct treatment of samples, electrically evoked or spontaneous field potentials were examined in the hippocampus and the neocortex of rat brain slices and in hippocampal cell cultures. In the hippocampus, a short-term increase in the excitability of neuronal networks and individual cells was observed in response to FB1 treatment. In some cases, the initially enhanced excitation was reversed presumably due to overactivation of neuronal networks. Normal spontaneous activity was found to be stimulated in hippocampal cell cultures. Seizure susceptibility was not affected in the neocortex of brain slices. For the verification of the results caused by direct treatment, effects of systemic administration of FB1 (7.5 mg/kg, i.p.) were also examined. Evoked field potentials recorded in vivo from the somatosensory cortex and cell activation measured by the c-fos technique in hippocampus and somatosensory cortex were analyzed. However, the hippocampal and cortical stimulatory effect detected in vitro could not be demonstrated by these in vivo assays. Altogether, the toxin enhanced the basic excitability of neurons and neuronal networks after direct treatment but there were no effects on the given brain areas after systemic treatment in vivo. Based on the observed in vitro FB1 effects and the lack of data on the penetration of FB1 across the blood-brain barrier, we assume that in vivo consequences of FB1 administration can be more prominent in case of perturbed blood-brain barrier functions.

The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours.

Deoxynivalenol (DON) or vomitoxin, is a trichothecene mycotoxin produced mainly by Fusarium graminearum and culmorum. Mycotoxins or secondary metabolic products of mold fungi are micro-pollutants, which may affect human and animal health. The neuronal and behavioural actions of DON were analysed in the present study. To address, which neurons can be affected by DON, the neuronal activation pattern following intraperitoneal injection of DON (1 mg/kg) was investigated in adult male rats and the results were confirmed in mice, too. DON-induced neuronal activation was assessed by c-Fos immunohistochemistry. DON injection resulted in profound c-Fos activation in only the elements of the reward system, such as the accumbens nucleus, the medial prefrontal cortex, and the ventral tegmental area. Further double labelling studies suggested that GABAergic neurons were activated by DON treatment. To study the behavioural relevance of this activation, we examined the effect of DON on feed intake as an example of reward-driven behaviours. Following DON injection, feed consumption was markedly reduced but returned to normal the following day suggesting an inhibitory action of DON on feed intake without forming taste-aversion. To further test how general the effect of DON on goal-directed behaviours is, its actions on maternal behaviour was also examined. Pup retrieval latencies were markedly increased by DON administration, and DON-treated mother rats spent less time with nursing suggesting reduced maternal motivation. In a supplementary control experiment, DON did not induce conditioned place preference arguing against its addictive or aversive actions. The results imply that acute uptake of the mycotoxin DON can influence the reward circuit of the brain and exert inhibitory actions on goal-directed, reward-driven behaviours. In addition, the results also suggest that DON exposure of mothers may have specific implications.