The mammalian claustrum, owing to its widespread connectivity with other forebrain structures, has been hypothesized to mediate functions that range from decision-making to consciousness
. Here we ...report that a homologue of the claustrum, identified by single-cell transcriptomics and viral tracing of connectivity, also exists in a reptile-the Australian bearded dragon Pogona vitticeps. In Pogona, the claustrum underlies the generation of sharp waves during slow-wave sleep. The sharp waves, together with superimposed high-frequency ripples
, propagate to the entire neighbouring pallial dorsal ventricular ridge (DVR). Unilateral or bilateral lesions of the claustrum suppress the production of sharp-wave ripples during slow-wave sleep in a unilateral or bilateral manner, respectively, but do not affect the regular and rapidly alternating sleep rhythm that is characteristic of sleep in this species
. The claustrum is thus not involved in the generation of the sleep rhythm itself. Tract tracing revealed that the reptilian claustrum projects widely to a variety of forebrain areas, including the cortex, and that it receives converging inputs from, among others, areas of the mid- and hindbrain that are known to be involved in wake-sleep control in mammals
. Periodically modulating the concentration of serotonin in the claustrum, for example, caused a matching modulation of sharp-wave production there and in the neighbouring DVR. Using transcriptomic approaches, we also identified a claustrum in the turtle Trachemys scripta, a distant reptilian relative of lizards. The claustrum is therefore an ancient structure that was probably already present in the brain of the common vertebrate ancestor of reptiles and mammals. It may have an important role in the control of brain states owing to the ascending input it receives from the mid- and hindbrain, its widespread projections to the forebrain and its role in sharp-wave generation during slow-wave sleep.
Recent studies revealed behaviorally defined sleep is conserved across broad species from insect to human. For evolutional analysis, it is critical to determine how homologous genes regulate the ...homologous function among species. Drosophila melanogaster shares numerous sleep related genes with mammals including Sik3, salt-inducible kinase 3, whose mutation caused long sleep both in mouse and fruit fly. The Drosophila rdgB (retinal degeneration B) encodes a membrane-associated phosphatidylinositol transfer protein and its mutation caused light-induced degeneration of photoreceptor cells. rdgB mutation also impaired phototransduction and olfactory behavior, indicating rdgB is involved in the normal neural transmission. Mammalian rdgB homologue, Pitpnm2 (phosphatidylinositol transfer protein membrane-associated 2) was discovered as one of SNIPPs (sleep-need index phosphoproteins), suggesting its role in sleep. Here, we show that rdgB is involved in sleep regulation in Drosophila. Pan-neuronal and mushroom body (MB) specific rdgB knockdown decreased nocturnal sleep. MB neurons play a dominant role, since the rescue of rdgB expression only in MB neurons in pan-neuronal knockdown reversed the sleep reducing effect of rdgB knockdown. These results revealed the sleep-related function of rdgB in Drosophila which may be conserved across species.
•rdgB RNAi in all neurons decreased sleep in Drosophila melanogaster.•Exclusion of mushroom body rescued sleep decrease by pan-neuronal rgdB RNAi.•rdgB RNAi specifically in mushroom body neurons decreased sleep during night.
•Vicarious social defeat stress diminishes cell survival rate in the hippocampus.•Vicarious social defeat stress produces no effect on cell proliferation rate.•Psychological stress influences ...new-born neuronal cell survival in the hippocampus.•Antidepressant fluoxetine rescues deficiencies in social behaviors and neurogenesis.•Validities of vicarious social defeat stress as a depression model is reinforced.
Increasing evidence has shown that adult hippocampal neurogenesis is closely related to the pathophysiological condition of depressive disorders. Recently, chronic social defeat stress paradigms have been regarded as important animal models of depression, accompanied with neural plastic changes in the hippocampus. However, little is known about influences of non-physical stress on neurogenesis. In the present study, we focused on the chronic vicarious social defeat stress paradigm and examined the effect of psychological stress on mouse hippocampal neurogenesis. Immediately after the chronic psychological stress, the cell survival rate in the dentate gyrus of the hippocampus was significantly diminished without modifying the cell proliferation rate. The decreased ratio in cell survival persisted for 4 weeks after the stress-loading period, while the differentiation and maturity of new-born neurons were identical to control groups. Furthermore, treatment with the chronic antidepressant fluoxetine reversed the social behavioral deficits and promoted new-born neurons survival. These results demonstrate that emotional stress in the vicarious social defeat stress paradigm influences neuronal cell survival in the hippocampus, which reinforces its validity as an animal model of depression.
Circadian rhythm is well conserved across species and relates to numerous biological functions. Circadian misalignment impairs metabolic function. Insulin signaling is a key modulator of metabolism ...in the fruit fly as well as mammals and its defects cause metabolic disease. Daily diet timing affects both circadian rhythmicities of behavior and metabolism. However, the relationship between the circadian clock and insulin signaling is still elusive. Here, we report that insulin signaling regulates circadian rhythm in Drosophila melanogaster. We found the insulin receptor substrate mutant, chico1, showed a shorter free-running circadian period. The knockdown of insulin receptor (InR), or another signaling molecule downstream of InR, dp110, or the expression of a dominant-negative form of InR resulted in the shortening of the circadian period and diminished its amplitude. The impairment of insulin signaling both in all neurons and restricted circadian clock neurons altered circadian period length, indicating that the insulin signaling plays a role in the regulation of circadian rhythm in clock cells. Among 3 insulin-like ligands expressed in the brain, dilp5 showed the largest effect on circadian phenotype when deleted. These results suggested that insulin signaling contributes to the robustness of the circadian oscillation and coordinates metabolism and behavior.
•Insulin receptor substrate mutant, chico1, displayed circadian rhythm phenotype.•Pan-neuronal inhibition of insulin receptor signaling shortened circadian cycle.•Inhibition of insulin signaling only in clock neurons altered circadian cycle.•Dilp5 is a major insulin receptor ligand for circadian effects.
Sleep behavior has been observed from non-vertebrates to humans.
Sleepy
mutation in mice resulted in a notable increase in sleep and was identified as an exon-skipping mutation of the
salt-inducible ...kinase 3 (Sik3)
gene, conserved among animals. The skipped exon includes a serine residue that is phosphorylated by protein kinase A. Overexpression of a mutant gene with the conversion of this serine into alanine (
Sik3-SA
) increased sleep in both mice and the fruit fly
Drosophila melanogaster
. However, the mechanism by which
Sik3-SA
increases sleep remains unclear. Here, we found that
Sik3-SA
overexpression in all neurons increased sleep under both light–dark (LD) conditions and constant dark (DD) conditions in
Drosophila
. Additionally, overexpression of
Sik3-SA
only in PDF neurons, which are a cluster of clock neurons regulating the circadian rhythm, increased sleep during subjective daytime while decreasing the amplitude of circadian rhythm. Furthermore, suppressing
Sik3-SA
overexpression specifically in PDF neurons in flies overexpressing
Sik3-SA
in all neurons reversed the sleep increase during subjective daytime. These results indicate that
Sik3-SA
alters the circadian function of PDF neurons and leads to an increase in sleep during subjective daytime under constant dark conditions.
Hippocampal neurons play a crucial role in memory formation. Accumulating evidence raises the possibility that hippocampal sharp-wave ripples (SW-Rs) are involved in memory consolidation. Here, we ...examined in an animal model of diabetes and found the amplitude of SW-Rs in diabetic mice were smaller than control group and were rescued by acute application of l-lactate, a major neural energy source. The cognitive impairment in diabetic mice was alleviated by intracerebroventricular l-lactate treatment. Our results suggested that l-lactate is important for hippocampal dysfunction in diabetes.
Microglia, as macrophages in the brain, are responsible for immune responses and synaptic remodeling. Although the function of microglia is regulated by circadian rhythms, it is still unclear whether ...microglia are involved in the generation and light entrainment of circadian rhythms of behavior. Here, we report that microglial depletion does not alter behavioral circadian rhythms. We depleted ~ 95% of microglia in the mouse brain by PLX3397, a CSF1R inhibitor, and analyzed the effect on the spontaneous behaviors of mice. We found that neither the free-running period under constant darkness nor light entrainment under jet-lag circumstances were influenced by the ablation of microglia. Our results demonstrate that the circadian rhythms of locomotor activity, an important output of the circadian clock in the brain, are likely a phenomenon not produced by microglia.
Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by ...gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities.
We have reported that the ingestion of a drink including winter savory extract (WSE) has an effect on core body temperature (CBT) and body surface temperature (BST) in people who experience cold ...sensitivity. In this study, to elucidate how the swallowing process contributes to changes in CBT and BST, experiments comparing the effects of WSE-drink and WSE-capsule were performed. We showed that a small amount of WSE-capsule did not affect CBT and BST, but WSE-drink (containing an equal amount of active principles in the WSE-capsule) induced significant changes in peripheral BST without changes in CBT. Moreover, WSE-drink with a higher concentration but equal amount of active principles induced significant changes in both CBT and BST. These results suggest that neurostimulation in the swallowing process after drinking WSE might greatly contribute to heat production and heat transfer (which is caused by peripheral vasodilation) independently of each other.
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We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full ...inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.
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