Early alterations in the MCH system link aberrant neuronal activity and sleep disturbances in a mouse model of Alzheimer's disease

Nature neuroscience

2023 May 15

Calafate, S;Özturan, G;Thrupp, N;Vanderlinden, J;Santa-Marinha, L;Morais-Ribeiro, R;Ruggiero, A;Bozic, I;Rusterholz, T;Lorente-Echeverría, B;Dias, M;Chen, WT;Fiers, M;Lu, A;Vlaeminck, I;Creemers, E;Craessaerts, K;Vandenbempt, J;van Boekholdt, L;Poovathingal, S;Davie, K;Thal, DR;Wierda, K;Oliveira, TG;Slutsky, I;Adamantidis, A;De Strooper, B;de Wit, J;
PMID: 37188873 | DOI: 10.1038/s41593-023-01325-4

Early Alzheimer's disease (AD) is associated with hippocampal hyperactivity and decreased sleep quality. Here we show that homeostatic mechanisms transiently counteract the increased excitatory drive to CA1 neurons in AppNL-G-F mice, but that this mechanism fails in older mice. Spatial transcriptomics analysis identifies Pmch as part of the adaptive response in AppNL-G-F mice. Pmch encodes melanin-concentrating hormone (MCH), which is produced in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH downregulates synaptic transmission, modulates firing rate homeostasis in hippocampal neurons and reverses the increased excitatory drive to CA1 neurons in AppNL-G-F mice. AppNL-G-F mice spend less time in rapid eye movement (REM) sleep. AppNL-G-F mice and individuals with AD show progressive changes in morphology of CA1-projecting MCH axons. Our findings identify the MCH system as vulnerable in early AD and suggest that impaired MCH-system function contributes to aberrant excitatory drive and sleep defects, which can compromise hippocampus-dependent functions.

The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

Nature communications

2023 Apr 17

Becker, LJ;Fillinger, C;Waegaert, R;Journée, SH;Hener, P;Ayazgok, B;Humo, M;Karatas, M;Thouaye, M;Gaikwad, M;Degiorgis, L;Santin, MDN;Mondino, M;Barrot, M;Ibrahim, EC;Turecki, G;Belzeaux, R;Veinante, P;Harsan, LA;Hugel, S;Lutz, PE;Yalcin, I;
PMID: 37069164 | DOI: 10.1038/s41467-023-37878-y

While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.

Synaptic Targets of Glycinergic Neurons in Laminae I-III of the Spinal Dorsal Horn

International journal of molecular sciences

2023 Apr 08

Miranda, CO;Hegedüs, K;Kis, G;Antal, M;
PMID: 37108107 | DOI: 10.3390/ijms24086943

A great deal of evidence supports the inevitable importance of spinal glycinergic inhibition in the development of chronic pain conditions. However, it remains unclear how glycinergic neurons contribute to the formation of spinal neural circuits underlying pain-related information processing. Thus, we intended to explore the synaptic targets of spinal glycinergic neurons in the pain processing region (laminae I-III) of the spinal dorsal horn by combining transgenic technology with immunocytochemistry and in situ hybridization accompanied by light and electron microscopy. First, our results suggest that, in addition to neurons in laminae I-III, glycinergic neurons with cell bodies in lamina IV may contribute substantially to spinal pain processing. On the one hand, we show that glycine transporter 2 immunostained glycinergic axon terminals target almost all types of excitatory and inhibitory interneurons identified by their neuronal markers in laminae I-III. Thus, glycinergic postsynaptic inhibition, including glycinergic inhibition of inhibitory interneurons, must be a common functional mechanism of spinal pain processing. On the other hand, our results demonstrate that glycine transporter 2 containing axon terminals target only specific subsets of axon terminals in laminae I-III, including nonpeptidergic nociceptive C fibers binding IB4 and nonnociceptive myelinated A fibers immunoreactive for type 1 vesicular glutamate transporter, indicating that glycinergic presynaptic inhibition may be important for targeting functionally specific subpopulations of primary afferent inputs.

A Sleep-Specific Midbrain Target for Sevoflurane Anesthesia

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

2023 Mar 24

Yi, T;Wang, N;Huang, J;Wang, Y;Ren, S;Hu, Y;Xia, J;Liao, Y;Li, X;Luo, F;Ouyang, Q;Li, Y;Zheng, Z;Xiao, Q;Ren, R;Yao, Z;Tang, X;Wang, Y;Chen, X;He, C;Li, H;Hu, Z;
PMID: 36961096 | DOI: 10.1002/advs.202300189

Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are still not completely understood. Here the authors show that sevoflurane activates a cluster of urocortin 1 (UCN1+ )/cocaine- and amphetamine-regulated transcript (CART+ ) neurons in the midbrain involved in its anesthesia. Furthermore, growth hormone secretagogue receptor (GHSR) is highly enriched in sevoflurane-activated UCN1+ /CART+ cells and is necessary for sleep induction. Blockade of GHSR abolishes the excitatory effect of sevoflurane on UCN1+ /CART+ neurons and attenuates its anesthetic effect. Collectively, their data suggest that anesthetic action of sevoflurane necessitates the GHSR activation in midbrain UCN1+ /CART+ neurons, which provides a novel target including the nucleus and receptor in the field of anesthesia.

Identification of brain-to-spinal circuits controlling the laterality and duration of mechanical allodynia in mice

Cell reports

2023 Mar 22

Huo, J;Du, F;Duan, K;Yin, G;Liu, X;Ma, Q;Dong, D;Sun, M;Hao, M;Su, D;Huang, T;Ke, J;Lai, S;Zhang, Z;Guo, C;Sun, Y;Cheng, L;
PMID: 36952340 | DOI: 10.1016/j.celrep.2023.112300

Mechanical allodynia (MA) represents one prevalent symptom of chronic pain. Previously we and others have identified spinal and brain circuits that transmit or modulate the initial establishment of MA. However, brain-derived descending pathways that control the laterality and duration of MA are still poorly understood. Here we report that the contralateral brain-to-spinal circuits, from Oprm1 neurons in the lateral parabrachial nucleus (lPBNOprm1), via Pdyn neurons in the dorsal medial regions of hypothalamus (dmHPdyn), to the spinal dorsal horn (SDH), act to prevent nerve injury from inducing contralateral MA and reduce the duration of bilateral MA induced by capsaicin. Ablating/silencing dmH-projecting lPBNOprm1 neurons or SDH-projecting dmHPdyn neurons, deleting Dyn peptide from dmH, or blocking spinal κ-opioid receptors all led to long-lasting bilateral MA. Conversely, activation of dmHPdyn neurons or their axonal terminals in SDH can suppress sustained bilateral MA induced by lPBN lesion.

A Novel Single Vector Intersectional AAV Strategy for Interrogating Cellular Diversity and Brain Function

bioRxiv : the preprint server for biology

2023 Feb 08

Hughes, AC;Pollard, BG;Xu, B;Gammons, JW;Chapman, P;Bikoff, JB;Schwarz, LA;
PMID: 36798174 | DOI: 10.1101/2023.02.07.527312

As the discovery of cellular diversity in the brain accelerates, so does the need for functional tools that target cells based on multiple features, such as gene expression and projection target. By selectively driving recombinase expression in a feature-specific manner, one can utilize intersectional strategies to conditionally promote payload expression only where multiple features overlap. We developed Conditional Viral Expression by Ribozyme Guided Degradation (ConVERGD), a single-construct intersectional targeting strategy that combines a self-cleaving ribozyme with traditional FLEx switches. ConVERGD offers benefits over existing platforms, such as expanded intersectionality, the ability to accommodate larger and more complex payloads, and a vector design that is easily modified to better facilitate rapid toolkit expansion. To demonstrate its utility for interrogating neural circuitry, we employed ConVERGD to target an unexplored subpopulation of norepinephrine (NE)-producing neurons within the rodent locus coeruleus (LC) identified via single-cell transcriptomic profiling to co-express the stress-related endogenous opioid gene prodynorphin ( Pdyn ). These studies showcase ConVERGD as a versatile tool for targeting diverse cell types and reveal Pdyn -expressing NE + LC neurons as a small neuronal subpopulation capable of driving anxiogenic behavioral responses in rodents.

Independent response modulation of visual cortical neurons by attentional and behavioral states

Neuron

2022 Sep 16

Kanamori, T;Mrsic-Flogel, TD;
PMID: 36137550 | DOI: 10.1016/j.neuron.2022.08.028

Sensory processing is influenced by cognitive and behavioral states, but how these states interact to modulate responses of individual neurons is unknown. We trained mice in a visual discrimination task wherein they attended to different locations within a hemifield while running or sitting still, enabling us to examine how visual responses are modulated by spatial attention and running behavior. We found that spatial attention improved discrimination performance and strengthened visual responses of excitatory neurons in the primary visual cortex whose receptive fields overlapped with the attended location. Although individual neurons were modulated by both spatial attention and running, the magnitudes of these influences were not correlated. While running-dependent modulation was stable across days, attentional modulation was dynamic, influencing individual neurons to different degrees after repeated changes in attentional states. Thus, despite similar effects on neural responses, spatial attention and running act independently with different dynamics, implying separable mechanisms for their implementation.

Postnatal age-differential ASD-like transcriptomic, synaptic, and behavioral deficits in Myt1l-mutant mice

Cell reports

2022 Sep 20

Kim, S;Oh, H;Choi, SH;Yoo, YE;Noh, YW;Cho, Y;Im, GH;Lee, C;Oh, Y;Yang, E;Kim, G;Chung, WS;Kim, H;Kang, H;Bae, Y;Kim, SG;Kim, E;
PMID: 36130507 | DOI: 10.1016/j.celrep.2022.111398

Myelin transcription factor 1 like (Myt1l), a zinc-finger transcription factor, promotes neuronal differentiation and is implicated in autism spectrum disorder (ASD) and intellectual disability. However, it remains unclear whether Myt1l promotes neuronal differentiation in vivo and its deficiency in mice leads to disease-related phenotypes. Here, we report that Myt1l-heterozygous mutant (Myt1l-HT) mice display postnatal age-differential ASD-related phenotypes: newborn Myt1l-HT mice, with strong Myt1l expression, show ASD-like transcriptomic changes involving decreased synaptic gene expression and prefrontal excitatory synaptic transmission and altered righting reflex. Juvenile Myt1l-HT mice, with markedly decreased Myt1l expression, display reverse ASD-like transcriptomes, increased prefrontal excitatory transmission, and largely normal behaviors. Adult Myt1l-HT mice show ASD-like transcriptomes involving astrocytic and microglial gene upregulation, increased prefrontal inhibitory transmission, and behavioral deficits. Therefore, Myt1l haploinsufficiency leads to ASD-related phenotypes in newborn mice, which are temporarily normalized in juveniles but re-appear in adults, pointing to continuing phenotypic changes long after a marked decrease of Myt1l expression in juveniles.

An inhibitory brainstem input to dopamine neurons encodes nicotine aversion

Neuron

2022 Aug 02

Liu, C;Tose, AJ;Verharen, JPH;Zhu, Y;Tang, LW;de Jong, JW;Du, JX;Beier, KT;Lammel, S;
PMID: 35921846 | DOI: 10.1016/j.neuron.2022.07.003

Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of α4β2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.

Early postnatal serotonin modulation prevents adult-stage deficits in Arid1b-deficient mice through synaptic transcriptional reprogramming

Nature communications

2022 Aug 27

Kim, H;Kim, D;Cho, Y;Kim, K;Roh, JD;Kim, Y;Yang, E;Kim, SS;Ahn, S;Kim, H;Kang, H;Bae, Y;Kim, E;
PMID: 36030255 | DOI: 10.1038/s41467-022-32748-5

Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that Arid1b-happloinsufficient (Arid1b+/-) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of Arid1b+/- mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult Arid1b+/- mice through transcriptional reprogramming.

Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome

Glia

2022 Jun 30

Aguilar, K;Comes, G;Canal, C;Quintana, A;Sanz, E;Hidalgo, J;
PMID: 35770802 | DOI: 10.1002/glia.24234

Leigh syndrome is a mitochondrial disease characterized by neurodegeneration, neuroinflammation, and early death. Mice lacking NDUFS4, a mitochondrial complex I subunit (Ndufs4 KO mice), have been established as a good animal model for studying human pathology associated with Leigh syndrome. As the disease progresses, there is an increase in neurodegeneration and neuroinflammation, thereby leading to deteriorating neurological symptoms, including motor deficits, breathing alterations, and eventually, death of the animal. However, despite the magnitude of neuroinflammation associated with brain lesions, the role of neuroinflammatory pathways and their main cellular components have not been addressed directly as relevant players in the disease pathology. Here, we investigate the role of microglial cells, the main immune cells of the CNS, in Leigh-like syndrome pathology, by pharmacologically depleting them using the colony-stimulating factor 1 receptor antagonist PLX3397. Microglial depletion extended lifespan and delayed motor symptoms in Ndufs4 KO mice, likely by preventing neuronal loss. Next, we investigated the role of the major cytokine interleukin-6 (IL-6) in the disease progression. IL-6 deficiency partially rescued breathing abnormalities and modulated gliosis but did not extend the lifespan or rescue motor decline in Ndufs4 KO mice. The present results show that microglial accumulation is pathogenic, in a process independent of IL-6, and hints toward a contributing role of neuroinflammation in the disease of Ndufs4 KO mice and potentially in patients with Leigh syndrome.

Daily changes in light influence mood via inhibitory networks within the thalamic perihabenular nucleus

Science advances

2022 Jun 10

Weil, T;Daly, KM;Yarur Castillo, H;Thomsen, MB;Wang, H;Mercau, ME;Hattar, S;Tejeda, H;Fernandez, DC;
PMID: 35687680 | DOI: 10.1126/sciadv.abn3567

Exposure to irregular lighting schedules leads to deficits in affective behaviors. The retino-recipient perihabenular nucleus (PHb) of the dorsal thalamus has been shown to mediate these effects in mice. However, the mechanisms of how light information is processed within the PHb remains unknown. Here, we show that the PHb contains a distinct cluster of GABAergic neurons that receive direct retinal input. These neurons are part of a larger inhibitory network composed of the thalamic reticular nucleus and zona incerta, known to modulate thalamocortical communication. In addition, PHbGABA neurons locally modulate excitatory-relay neurons, which project to limbic centers. Chronic exposure to irregular light-dark cycles alters photo-responsiveness and synaptic output of PHbGABA neurons, disrupting daily oscillations of genes associated with inhibitory and excitatory PHb signaling. Consequently, selective and chronic PHbGABA manipulation results in mood alterations that mimic those caused by irregular light exposure. Together, light-mediated disruption of PHb inhibitory networks underlies mood deficits.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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