bims-meneob 2026-02-15 papers

bims-meneob

Biomed News

on Metabolism Neuroscience Obesity

Issue of 2026–02–15
eighteen papers selected by
Mohammed K Hankir, Trinity College Dublin

The sodium leak channel NALCN in Drd2+ striatal neurons regulates neuronal excitability, locomotion and food-seeking in a sex-dependent manner.
Population decoding of sound source location by receptive field neurons in the mouse superior colliculus.
Learning of visual sequences by neurons in the human hippocampus.
AUDIOGENIC SEIZURE SUPPRESSION BY VENTRAL TEGMENTAL AREA STIMULATION.
Galanin receptor 1 expressing neurons in hippocampal-prefrontal circuitry modulate goal directed attention and impulse control.
Circuit organization of the forelimb-related M2-to-M1 corticocortical pathway in the mouse.
Selective Deletion of FGFR1 in AgRP Neurons Impairs Energy Homeostasis Under High-Fat Diet in Mice.
Differential Autoregulation of Serotonin Secretion at Different Structures of Serotonergic Neurons.
Effects of Spin4 ablation in aging mice: body composition, bone density, and malignancy prevalence.
F26BP enables control of glycolysis rate independent of energy state.
Physical activity promotes gut adaptation, nutrient responsiveness, and sensitivity to gut peptides in male mice.
The pyrogenic mediator prostaglandin E2 elicits warmth seeking via EP3 receptor-expressing parabrachial neurons: a potential mechanism of chills.
Hormonal control of postmitotic neuronal identity.
Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding.
GHSR agonism increases blood glucose but delays food intake in GHSR hyperresponsive rats.
Comparison of Various Dosages of Escitalopram on Anxiety-like Behavior and Body Weight in Male Rats under Severe Chronic Stress.
PLCβs are recruited to the plasma membrane in macrophages by both Gβγ and Gα q.
IGF1 peptide targets Rett Syndrome astrocytes to degrade IGF binding protein, rescue synaptogenesis and restore mitochondrial function.

Neuropsychopharmacology. 2026 Feb 11.

The sodium leak channel NALCN in Drd2+ striatal neurons regulates neuronal excitability, locomotion and food-seeking in a sex-dependent manner.

Laia Castell, Claire Naon, Angelina Rogliardo, Fabien Ducrocq, Leila Makrini, Alexandra Typou, Maëlle Avrillon, Audrey Mignon, Claire Bernat, Philippe Lory, Federica Bertaso, Arnaud Monteil, Clémentine Bosch-Bouju, Emmanuel Valjent.

The sodium leak channel NALCN is an important modulator of cell excitability. Studies so far demonstrated the critical role of this highly conserved channel in the generation and maintenance of pacemaker activity in cells with spontaneous firing, such as cardiomyocytes, adrenal cells, or neurons. However, the physiological importance of NALCN for neurons with no spontaneous firing has been largely overlooked and remains unknown. Yet, Drd2-expressing striatal projection neurons (SPNs) show an enriched expression of NALCN while they are highly hyperpolarized neurons. Considering that pathogenic variants of NALCN in human result in severe pathological conditions with symptoms that include cognitive and motor impairments, we hypothesized that NALCN in Drd2-SPNs was necessary for their correct signal integration and consequently striatal-associated behaviors. Here, we investigated the impact of NALCN deletion in Drd2-SPNs in both male and female mice. Unexpectedly, we found that only male mice with deletion of NALCN in Drd2-expressing neurons exhibited enhanced locomotor responses to novel environment and reduced motivation in food-seeking tasks, while female mice were unaffected in their behavior. Similarly, electrophysiological recordings of SPNs revealed significant sex differences, with male SPNs lacking NALCN exhibiting altered membrane properties and increased excitability, while females showed only subtle changes. Finally, we found that eticlopride-induced catalepsy and signaling events were differently altered by NALCN deletion in Drd2-SPNs male and female mice. This work constitutes the first evidence that NALCN in Drd2-SPNs participates to striatal function and may be a key modulator of response to antidopaminergic treatments, with significant sex differences.

DOI: https://doi.org/10.1038/s41386-026-02363-9
bioRxiv. 2026 Jan 27. pii: 2026.01.26.701861. [Epub ahead of print]

Population decoding of sound source location by receptive field neurons in the mouse superior colliculus.

Brian R Mullen, Alan M Litke, David A Feldheim.

Identifying the location of a sound source in a complex environment and assessing its importance can be crucial for survival. The superior colliculus (SC), a midbrain structure involved in sensorimotor functions, contributes to sound localization and contains auditory responsive neurons that have spatially restricted receptive fields (RFs) that are organized into a topographic map along the azimuth. However, individual auditory SC neurons have large spatial RFs, are noisy, and do not respond to the same stimulus at each trial. Therefore, when an animal is presented with a "single trial" sound, and it needs to rely on a single neuron to locate the sound source direction, the location measurement may be erroneous, missing, or have poor spatial resolution. It is expected that a more reliable and accurate determination of the sound source location will come from a population of neurons. We therefore built a population pattern Maximum Likelihood Estimation (MLE) decoder to build a model that can accurately predict the location of a stimulus given the population response. We compared three models that use either strict firing rate (FR), weighting based on equal (EW) or mutual information (MIW) and show that the MIW model works best, needing only 92 neurons to localize a stimulus with behaviorally relevant precision. Furthermore, by comparing the model's fit using the responses from non-RF and RF auditory neurons, we show that only RF neurons contain the information needed to localize a sound source. These results are consistent with the hypothesis that the SC uses a population of RF neurons to determine sound source location.
Author Summary: Being able to tell where a sound is coming from and how important it is can be critical for survival. The superior colliculus, a midbrain region involved in orienting behaviors, contains neurons that respond best to sounds coming from specific locations. This suggests that the combined activity of many neurons in the SC is used to determine sound location from a single sound event. To test this idea, we modeled responses from mouse SC neurons while sounds were played from different positions in space, both along the elevation and horizon. A model that weighted the most informative neurons performed best in both directions needing only 92 neurons to localize a stimulus with behaviorally relevant precision along the azimuth. Comparing the model's fit using the responses from non-RF and RF auditory neurons, we show that only RF neurons contain the information needed to localize a sound source Overall, our findings show that the SC can accurately locate sounds in both horizontal and vertical space using a population-based strategy, providing a simple and effective solution for rapid sound localization.

DOI: https://doi.org/10.64898/2026.01.26.701861
bioRxiv. 2026 Feb 03. pii: 2025.03.04.641300. [Epub ahead of print]

Learning of visual sequences by neurons in the human hippocampus.

Tibin John, Yajun Zhou, Ayman Aljishi, Bastian Rieck, Nicholas B Turk-Browne, Eyiyemisi C Damisah.

Time is a critical component of memory and yet how the hippocampus incorporates temporal information with the sensory contents of memories remains unclear. We hypothesized that the hippocampus can learn arbitrary sequences through rapid changes in the tuning and population geometry of individual neurons to mirror the sequence structure. We recorded single-unit activity from 134 neurons in the hippocampus of 17 patients with epilepsy while they viewed sequences of visual scenes that were presented repeatedly in the same order by looping from the end to start. As the sequence repeated, hippocampal neurons that were initially responsive to one scene in the sequence began responding to the other scenes proportional to their temporal proximity. The population vectors of spiking activity across recorded hippocampal neurons for each scene came to form a high-dimensional ring topology that encoded the circular structure of the sequence in a manner that preserved the serial order of the scenes. These effects were not observed when sequences were scrambled upon each repetition to destroy temporal structure, nor in brain regions outside of the hippocampus for both structured and random sequences. These findings suggest that temporal structure governs the representation of sensory stimuli in human hippocampal neurons.

DOI: https://doi.org/10.1101/2025.03.04.641300
Georgian Med News. 2025 Dec; 31-37

AUDIOGENIC SEIZURE SUPPRESSION BY VENTRAL TEGMENTAL AREA STIMULATION.

I Bilanishvili, M Barbakadze, N Nikabadze, G Andronikashvili, Z Nanobashvili.

The audiogenic seizure (AGS) model is one of several experimental models used to study epilepsy and identify underlying mechanisms. Dopamine plays an important role in epileptogenesis and dopaminergic neurons of ventral tegmental area (VTA) have extensive connections with many brain structures. Despite of this there are no data on the influence of this structure on the audiogenic seizure responses of the brain. The main aim of our study was to investigate the influence of the VTA on the development of audiogenic seizure reactions in genetically epilepsy-prone rats. The novelty of these article lies not only in the observation of changes in the development/course of audiogenic seizure reactions caused by stimulation of the VTA, but also in taking into account the localization of the epileptogenic focus, which, in our opinion, is especially important for the scientific analysis of this type of research. The inferior and superior colliculus has prominent descending projections to several areas of the reticular formation, which may sub serve the direct AGS efferent pathway. The experiments conducted showed that in response to stimulation of the VTA, the latency and duration of the first wild run do not undergo significant changes. The experiments showed a significant increase in the duration of the pause between the first and second wild runs and a significant decrease in the duration of the second wild run. Furthermore, we observed a significant decrease in behavioral seizure activity after the second wild run, leading to its complete disappearance. Structures receiving synaptic inputs from the ventral tegmental area deserve special attention. One such structure is the reticular nucleus of the thalamus (TRN). It has been shown that stimulation of TRN causes inhibition of neurons in those brainstem structures that are involved in motor reactions of the spinal cord. Therefore, it can be hypothesized that the TRN modulate the brainstem regions responsible for motor responses during audiogenic seizures. From our results we can conclude: The VTA plays an important role in epileptogenesis, which is apparently associated with the inhibitory effect of dopamine on the motor manifestations of seizures. Therefore, VTA as a brain dopaminergic nucleus, may be a suitable target for DBS anticonvulsant action.
Neuropsychopharmacology. 2026 Feb 11.

Galanin receptor 1 expressing neurons in hippocampal-prefrontal circuitry modulate goal directed attention and impulse control.

Fany Messanvi, Vladimir Visocky, Carolyn Senneca, Kathleen Berkun, Maansi Taori, Sean P Bradley, Huikun Wang, Hugo A Tejeda, Yogita Chudasama.

Neuropeptides like galanin are increasingly recognized as modulators of cognitive pathways. Galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. Recently, we discovered that direct pharmacological stimulation of galanin receptor type 1 (GalR1) in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) caused opposing effects on attention and impulse control behaviors. In the present study, we investigate how neurons expressing GalR1 in these two areas differentially contribute to these behaviors. First, using multiplex fluorescent in situ-hybridization, we established that GalR1 is predominantly expressed in glutamatergic neurons in both the vPFC and vHC. Rats were assessed in their visuospatial attention and impulse control behaviors using the 5-Choice task. We developed a novel viral approach to gain genetic access to GalR1-expressing neurons in the vPFC and vHC and found that optogenetic excitation of GalR1 expressing neurons in the vPFC, but not vHC, selectively disrupted attention. Finally, using fiber photometry, we measured bulk calcium dynamics in GalR1-expressing neurons and discovered that GalR1- expressing neurons in the vPFC and vHC showed opposing activity; increased activity in neurons in the vPFC corresponded to correct, attentive actions, whereas activity in the vHC was associated with errors. This region- and response-specific intrinsic activity of galanin, mediated by subclasses of neurons in frontotemporal circuitry participates in shaping the expression of executive-control behaviors that often go awry in various disorders of mental health.

DOI: https://doi.org/10.1038/s41386-026-02360-y
bioRxiv. 2026 Feb 05. pii: 2026.02.03.703577. [Epub ahead of print]

Circuit organization of the forelimb-related M2-to-M1 corticocortical pathway in the mouse.

Louis Richevaux, Rita Fischer, Miraya Baid, Gordon M G Shepherd.

Communication from secondary (M2, premotor) to primary (M1) motor cortex is implicated in forelimb motor control. We investigated the underlying synaptic circuits in this corticocortical pathway in male and female mice using cell-type-specific optogenetic-electrophysiology methods, focusing on identifying the cell-type-specific synaptic connections in the excitatory and feedforward inhibitory circuits impinging on cervically projecting M1 corticospinal neurons. In forelimb M1 brain slices, recordings from layer 5B corticospinal neurons during brief photostimulation of M2 axons showed strong monosynaptic excitatory currents that, although accompanied by potent feedforward inhibitory currents, were capable of evoking action potentials (APs) in most neurons. In contrast, responses in layer 2/3 pyramidal neurons were generally much weaker. Parvalbumin-expressing neurons (PV), particularly in deeper layers, showed direct excitation from M2 axons without feedforward inhibition, and could fire APs robustly. Somatostatin (SST) neurons received generally weak inputs, whereas VIP and Ndnf neurons received stronger excitation and inhibition from M2 axons. Corticospinal neurons received little or no local inhibition from Ndnf and VIP interneurons, but relatively strong soma-targeting PV and dendrite-targeting SST inhibitory inputs, as functionally imaged by laser-scanning synaptic input mapping (sCRACM). The domains of PV and SST inputs were partly overlapping around the corticospinal somata, but broader for PV and more vertical for SST inputs. Collectively, the results provide a working model for the cell-type-specific synaptic circuits of this top-down corticocortical pathway, organized around direct M2 excitation and PV-mediated inhibition of M1 corticospinal neurons.

DOI: https://doi.org/10.64898/2026.02.03.703577
Mol Metab. 2026 Feb 10. pii: S2212-8778(26)00016-5. [Epub ahead of print] 102332

Selective Deletion of FGFR1 in AgRP Neurons Impairs Energy Homeostasis Under High-Fat Diet in Mice.

Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang.

   BACKGROUND: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.
METHODS: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.
RESULTS: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression.
CONCLUSION: Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis.

Keywords:  AgRP Neuron; Energy Homeostasis; FGFR1; High Fat Diet

DOI:  https://doi.org/10.1016/j.molmet.2026.102332
Int J Mol Sci. 2026 Jan 23. pii: 1150. [Epub ahead of print]27(3):

Differential Autoregulation of Serotonin Secretion at Different Structures of Serotonergic Neurons.

Citlali Trueta, Montserrat G Cercós.

  Serotonin (5-HT) performs a wide range of neuromodulatory actions in the nervous system, including the regulation of the neurons that release it, by activation of several types of autoreceptors that modulate their electrical activity, as well as its own release. 5-HT neurons release serotonin in different manners from different subcellular structures, including the presynaptic terminals, the somatodendritic region and the axons. The different releasing structures of the same neurons have different types of autoreceptors, which exert differential auto-regulatory effects. Here we critically review the evidence of serotonergic autoregulation, both in mammals and in invertebrates, with particular emphasis on studies of serotonergic Retzius neurons of the leech, which have been a model for detailed studies of serotonin secretion from different neuronal structures. In these neurons serotonin produces different and even opposite effects on different releasing structures, such as the presynaptic terminals and the soma, through activation of different types of autoreceptors, thus increasing the specialization of the mechanisms that regulate exocytosis from each site. The differential autoregulation of serotonin release from different structures enables a single neuron to exert a variety of different functions in the nervous system.

Keywords:  autoinhibition; autoreceptor; autoregulation; feedback; leech; presynaptic terminal; raphe nuclei; serotonin; somatic secretion

DOI:  https://doi.org/10.3390/ijms27031150
bioRxiv. 2026 Feb 08. pii: 2026.02.05.704000. [Epub ahead of print]

Effects of Spin4 ablation in aging mice: body composition, bone density, and malignancy prevalence.

Julian C Lui, Isabelle Hannula, Arun Rama-Krishnan, Lijin Dong, Jeffrey Baron.

Many overgrowth syndromes are associated with increased risk of tumorigenesis and malignancies. Our group recently identified a frameshift variant in histone reader SPIN4 located on the X chromosome to be a new genetic cause for human overgrowth. In the current study, we investigated the prevalence of malignancies, along with body weight, body length, body composition and bone mineral density, in Spin4 knockout mice at 18 months of age. We found that male mice lacking Spin4 have increased number of tumors and increased body length, while body weight, body composition and bone mineral density were comparable with wild-type mice. We also analyzed publicly available expression data in various types of human cancers and looked for increased or decreased expression of genes that are implicated in overgrowth syndromes and act through epigenetic mechanisms. We found that the expression of SPIN4, EZH2, and DNMT3A to be elevated in many human cancers compared to the corresponding non-malignant tissue samples. Taken together, our current findings confirm that loss of SPIN4 causes overgrowth in mice (in terms of body length) and is associated with increased prevalence in neoplasia; but does not appear to affect adiposity or bone density.

DOI: https://doi.org/10.64898/2026.02.05.704000
bioRxiv. 2026 Jan 31. pii: 2026.01.31.703051. [Epub ahead of print]

F26BP enables control of glycolysis rate independent of energy state.

Megan M Kober, Xinyi Yang, Bradley A Webb, Denis V Titov.

Glycolysis is a conserved metabolic pathway that produces ATP and biosynthetic precursors. Multiple allosteric regulators control glycolytic enzymes in vitro . For example, phosphofructokinase (PFK) is allosterically regulated by fructose-2,6-bisphosphate (F26BP), ATP, ADP, AMP, citrate, acyl-CoA, and inorganic phosphate. It is not well understood which properties of homeostasis are enabled by each of these regulators, and whether they perform redundant or distinct functions. Using mathematical modeling and experiments with human cells lacking F26BP, we demonstrate that F26BP alters glycolytic rate independent of cellular ATP demand-a unique function not shared by other regulators. We also identified several downstream glycolytic intermediates as novel regulators of F26BP levels. Our findings clarify the role of F26BP as a unique regulator that controls the glycolytic rate independently of the cellular energy state in response to hormone and biosynthetic precursor levels. The F26BP regulatory circuit enables respiratory fuel selection and biosynthesis from glycolytic intermediates.

DOI: https://doi.org/10.64898/2026.01.31.703051
EBioMedicine. 2026 Feb 10. pii: S2352-3964(26)00033-2. [Epub ahead of print]125 106152

Physical activity promotes gut adaptation, nutrient responsiveness, and sensitivity to gut peptides in male mice.

Cecilie Bæch-Laursen, Jon Vergara Ucin, Katrine Douglas Galsgaard, Jesus Llana, Hannelouise Kissow, Jens Frederik Rehfeld, Jens Juul Holst, Bente Klarlund Pedersen, Paula Sanchis.

   BACKGROUND: Physical activity helps maintain a healthy stable body weight. One mechanism underlying this beneficial effect could be the improved coupling between energy intake and expenditure, since hunger and satiety are better regulated in active individuals. Whether this enhancement of appetite control by exercise is reflected in overall adaptations in the gut and gut-brain communication remains poorly defined.
METHODS: We investigated how increased physical activity alters gut morphology, intestinal endocrine function, and central appetite signalling in C57BL/6NRJ male mice fed ad-libitum chow diet. We assessed intestinal growth, L-cell density, and glucose-stimulated endocrine secretion, as well as circulating levels and gene expression of gut derived peptide hormones. Additionally, we quantified neuronal activity in the brainstem dorsal vagal complex following a fasting-refeeding intervention and examined the effects of PYY, CCK, ghrelin, and GLP-1 administration on food intake in sedentary and physically active mice. Depending on the dataset, unpaired or paired Student's t-tests, two-way ANOVA followed by Bonferroni's post hoc test, simple linear regression or a linear mixed-effects model were applied. Statistical significance was set at P < 0.05.
FINDINGS: Physical activity induced a slight growth of the small intestine, increased L-cell density, and enhanced glucose-stimulated GLP-1 secretion. It altered the circulating levels of PYY and ghrelin and increased the dynamic regulation of neuronal activity in the area postrema and nucleus tractus solitarius. Active mice displayed greater sensitivity to gut-derived hormones PYY, CCK, and ghrelin exerting amplified and prolonged effects on food intake, whereas native GLP-1 showed no effect, likely due to its short half-life. Physical activity prevented post-fasting hyperphagia, thereby promoting sustained maintenance of fasting-induced weight loss.
INTERPRETATION: The findings demonstrate that physical activity promotes adaptations in the gut and gut-to-brain communication possibly enhancing the responsiveness to appetite-regulating signals. Such adaptations may strengthen the alignment between energy intake and expenditure to support body weight maintenance.
FUNDING: This study was supported by Novo Nordisk Foundation (0059436) and Trygfonden Centre for Physical Activity Research (101390, 20045, 125132, and 177225). P.S. is supported by Lundbeck Foundation (R380-2021-1300).

Keywords:  Appetite regulation; Endocrine signalling; Energy homeostasis; Exercise; Food intake; Gut physiology; Gut-to-brain communication; Hunger; Physical activity; Satiety; Small intestine; Stable body weight

DOI:  https://doi.org/10.1016/j.ebiom.2026.106152
J Physiol. 2026 Feb 10.

The pyrogenic mediator prostaglandin E2 elicits warmth seeking via EP3 receptor-expressing parabrachial neurons: a potential mechanism of chills.

Takaki Yahiro, Yoshiko Nakamura, Kazuhiro Nakamura.

  Seeking warmth during infection is a sickness behaviour that contributes to the development of fever and is often accompanied by chills. However, the central mechanism underlying this behaviour remains unknown. We recently reported two ascending thermosensory neuronal pathways from the lateral parabrachial nucleus (LPB) of the pons that drive thermoregulatory behaviours in hot and cold environments: one pathway to the preoptic area (POA), a thermoregulatory centre, mediates heat avoidance, whereas the other to the central amygdaloid nucleus (CeA), a limbic emotion centre, mediates cold avoidance. Here we investigated the role of prostaglandin E2 (PGE2), a pyrogenic mediator produced during infection, in the LPB-mediated mechanism of thermoregulatory behaviour in rats. Thermal preference tests and in vivo physiological recordings revealed that PGE2 acting on the prostaglandin EP3 receptor (EP3R) in the LPB elicits behaviour that prefers warmth to a thermoneutral temperature, thereby contributing to an increase in body core temperature. However, it does not elicit brown adipose tissue thermogenesis, an autonomic febrile response. Notably, we discovered that EP3R-expressing LPB neurons (LPBEP3R neurons) project numerous axons to the CeA, but few to the POA. Functional neuronal tracing combined with immunostaining of Fos, a marker for neuronal activation, revealed that LPBEP3R→CeA neurons are activated by cold ambient temperature and constitute the majority of the cold-transmitting LPB→CeA neuronal population mediating cold avoidance. These results indicate that PGE2 action on LPBEP3R neurons during infection elicits warmth-seeking behaviour by augmenting their cold sensory transmission to the CeA, which potentially produces the unpleasant cold sensation of chills. KEY POINTS: Seeking warmth during infection is a commonly observed sickness behaviour that contributes to the development of fever, often accompanied by chills. Prostaglandin E2 (PGE2), a pyrogenic mediator, elicits warmth-seeking behaviour in rats by acting on prostaglandin EP3 receptor (EP3R)-expressing neurons in the lateral parabrachial nucleus (LPB) of the pons (LPBEP3R neurons). This PGE2 action does not elicit thermogenesis in brown adipose tissue, an autonomic febrile response. LPBEP3R neurons transmit cutaneous cold sensory signals to the limbic emotion centre, central amygdaloid nucleus (CeA), but scarcely innervate the thermoregulatory centre, preoptic area. These results indicate that PGE2 acting on LPBEP3R neurons during infection elicits warmth-seeking behaviour by augmenting cold sensory transmission to the CeA, which is a potential mechanism of chills.

Keywords:  amygdala; behaviour; chills; emotion; fever; prostaglandin; somatosensory systems; thermoregulation

DOI:  https://doi.org/10.1113/JP289466
bioRxiv. 2026 Jan 29. pii: 2026.01.28.702037. [Epub ahead of print]

Hormonal control of postmitotic neuronal identity.

Adil Rashid Wani, Rahail Ashraf, Riley Woerner, Zoe Marriner, Michael Velasquez, Tulaib Azam, Qussin Joo, Monica Dus, Mubarak Hussain Syed.

The Drosophila central complex is a brain region that coordinates complex behaviors through precisely wired circuits composed of diverse neuronal subtypes. Dorsal fan-shaped body (dFB) neurons integrate internal-state signals to regulate sleep, feeding, and energy homeostasis, yet how dFB subtypes are specified and maintained remains unclear. More importantly, how a developmental transcription factor regulates neuronal identity remains poorly understood. Here, we investigate the developmental origin and post-mitotic regulation of neuronal identity in dFB subtypes labeled by the 84C10 driver, which innervates layers 6-7 of the fan-shaped body and contributes to nutrient sensing and metabolic adaptation. Using lineage tracing, clonal analysis, and birth-dating, we show that 84C10 dFB neurons derive primarily from the DL1 type II neural stem cell lineage, with a minor contribution from DM4, and are generated during a late larval temporal window after ∼48 h after larval hatching (ALH). These late-born neurons maintain expression of ecdysone-responsive transcription factor E93 into adulthood. Selective postmitotic knockdown of E93 in mature 84C10 neurons causes progressive neuronal loss, ectopic expansion of axonal arborizations across fan-shaped body layers, and downregulation of the vesicular glutamate transporter vGLUT. These circuit defects are accompanied by a failure to accumulate higher fat to lean mass in response to high-sugar feeding. Together, our results demonstrate that a late temporal transcription factor, E93, is retained post-mitotically to preserve neuronal survival, layer-specific connectivity, and neurotransmitter identity in a behaviorally relevant dFB population, revealing how developmental programs are repurposed to sustain the long-term function of adult behavioral circuits.

DOI: https://doi.org/10.64898/2026.01.28.702037
J Neurosci. 2026 Feb 11. pii: e1422252026. [Epub ahead of print]

Divergent Roles of Nucleus Accumbens D1- and D2-MSNs in Regulating Hedonic Feeding.

Chase A Carter, Samhitha S Pudipeddi, Pierre Llorach, Jessica J Walsh, Daniel J Christoffel.

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre-driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of high-fat diet only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption.Significance Statement Obesity and metabolic disorders are partly driven by dysregulated motivation for palatable foods, yet the neural circuits underlying hedonic feeding are not fully understood. This study shows that nucleus accumbens medium spiny neurons have differential, sex-specific roles in high-fat intake: D1-MSN activity suppresses intake in male mice, while D2-MSNs promote consumption in female mice. Using chemogenetics, optogenetics, and fiber photometry, we establish a causal link between MSN activity and hedonic feeding. These findings expand previous models of reward processing and highlight the experience and sex- dependent roles of MSN subtypes. By defining cell-type-specific contributions to non-homeostatic eating, this work offers key insight into the neural basis of hedonic intake and informs strategies for targeted intervention in obesity and related conditions.

DOI: https://doi.org/10.1523/JNEUROSCI.1422-25.2026
J Neuroendocrinol. 2026 Feb;38(2): e70143

GHSR agonism increases blood glucose but delays food intake in GHSR hyperresponsive rats.

Philippe Zizzari, Olalla Ramírez-Penas, Véronique Pons, Matilda Oujezdska, Ange-Louis Sammarcelli, Thomas Saint-Yves, Inès Chevallier-Chantepie, Lucile Baussart, Vanessa Nhan, Adèle Phalip, Céline Gales, Daniela Cota, Florence Noble, Jacques Pantel.

  Severe calorie restriction in mouse models has highlighted the crucial role of the ghrelin system in maintaining glycemia and promoting survival. We hypothesized that if ghrelin acts as a survival signal, enhancing the responsivity of the GH secretagogue receptor (GHSR) should favor GHSR protective responses. To test this, we used rats with genetically enhanced GHSR sensitivity (GhsrQ343X) and wild-type littermate controls and examined their acute responses to pharmacological challenges. Consistent with our hypothesis, GhsrQ343X rats, despite normal glucose and insulin tolerance, exhibited a significant increase in blood glucose in response to GHSR agonism, accompanied by elevated counter-regulatory hormones including corticosterone. Concurrently, these rats displayed a notable decrease in locomotor activity and delayed feeding response. Also, GHSR agonism partially altered the cocaine-induced hyperlocomotion of GhsrQ343X rats while they showed unaltered locomotor sensitization to cocaine. At the cellular level, functional studies indicated that the GhsrQ343X mutation prolongs ghrelin-induced GHSR-G protein canonical signaling. Altogether, in a model of increased GHSR sensitivity, GHSR agonist stimulation was sufficient to promote a robust blood glucose increase, while the acute feeding response was delayed in a context of unexpected hypolocomotor response. This mechanism may have implications for severe states of undernutrition such as restrictive anorexia nervosa.

Keywords:  GHSR responsivity; GPCR; food intake; ghrelin; glucose counter regulation; locomotion

DOI:  https://doi.org/10.1111/jne.70143
Adv Biomed Res. 2025 ;14 157

Comparison of Various Dosages of Escitalopram on Anxiety-like Behavior and Body Weight in Male Rats under Severe Chronic Stress.

Maryam Radahmadi, Zahra Farahbakhsh.

   Background: Stress and escitalopram impact mood and various physiological systems. The present study aimed to compare the protective effects of different dosages of escitalopram on anxiety-like behavior and body weight in male rats subjected to severe chronic stress.
Materials and Methods: Rats were randomly divided into groups: control, stress, sham, escitalopram (10 mg/kg and 20 mg/kg), and stress-escitalopram (10 mg/kg and 20 mg/kg). Restraint stress was induced 6h/day/14 days, and escitalopram was administered concurrently. The number of open arm entries (OAE%) and the total time spent in the open arms (OAT%) were assessed using the elevated plus maze test.
Results: There were significant reductions in latency, OAT%, and OAE% within the stressed group. OAT% showed a notable increase in the Stress-Escitalopram10 and Stress-Escitalopram 20 groups when compared to the stressed group. Both OAT% and OAE% significantly decreased in the Stress-Escitalopram20 compared to the Stress-Escitalopram10. There were significant reductions in body weight differences across all experimental groups. The body weight in the Stress-Escitalopram20 was significantly lower than that of the group receiving only escitalopram at a dosage of 20 mg/kg.
Conclusion: Escitalopram did not induce significant changes in anxiety-like behavior under stress-free conditions. The simultaneous administration of escitalopram, particularly at a dosage of 10 mg/kg, exhibited a protective effect in reversing of anxiety-like behavior under stressed conditions. Both doses of escitalopram resulted in a reduction of body weight in both stress and stress-free conditions, highlighting the dual behavioral and physiological effects of escitalopram. These findings offer novel insights into the dose-specific effects and potential side effects of escitalopram, thereby informing its clinical application for stress-related disorders.

Keywords:  Anxiety; elevated plus maze; escitalopram; rat; stress

DOI:  https://doi.org/10.4103/abr.abr_467_24
bioRxiv. 2026 Jan 31. pii: 2026.01.28.702352. [Epub ahead of print]

PLCβs are recruited to the plasma membrane in macrophages by both Gβγ and Gα q.

Maria E Falzone, Priyam Banerjee, Roderick MacKinnon.

PLCβ enzymes cleave PIP2 from the plasma membrane, producing IP3 and DAG, which regulate intracellular Ca 2+ levels and protein kinase C activity, respectively. They are regulated by GPCR signaling through the G proteins Gβγ and Gα q and have been shown to function as coincidence detectors for dual stimulation of Gα q and Gα i -coupled receptors via these G proteins. PLCβs are aqueous-soluble enzymes, but partition onto the membrane surface to access their lipid substrate. We previously demonstrated that membrane recruitment and orientation of the catalytic core on the membrane surface underlie Gβγ-dependent regulation of PLCβ enzymes. Using macrophages as a model system, where PLCβ signaling is essential for responses to infection and tissue injury, we investigated the contribution of Gβγ-dependent regulation and membrane recruitment of PLCβ in the context of endogenous signaling. By measuring Ca 2+ mobilization, we demonstrate that both Gα i and Gαq-coupled receptors independently stimulate PLCβ activity, illustrating that Gβγ alone is sufficient to activate PLCβ in certain contexts. Using total internal reflection and stimulated emission depletion microscopy, we demonstrate that most of the PLCβ3 in the cell is localized away from the plasma membrane at rest but is rapidly recruited to the plasma membrane upon stimulation by both Gα i and Gα q -coupled receptors, illustrating that both Gβγ and Gα q recruit PLCβ to the plasma membrane. These results support an updated model for G protein-dependent regulation of PLCβ enzymes, where Gβγ-induced regulation in the absence of Gα q is context dependent and dictated by the local concentration of receptor, G proteins, and PLCβ.
Significance Statement: PLCβ enzymes are critical mediators of signal transduction with roles in neuronal, cardiac, and immunological signaling. Despite this importance, many aspects of their function and regulation remain poorly understood. PLCβs are aqueous soluble but must partition onto the membrane surface to access their lipid substrate, which enables regulation at the partitioning step, the catalytic step, or both. We previously demonstrated that membrane recruitment and orientation of the catalytic core on the membrane surface underlie the PLCβ regulation by one effector, Gβγ. Using macrophages as a model system for physiological signaling, we demonstrate that Gβγ is capable of independently activating PLCβ via membrane recruitment under the conditions of endogenous signaling.

DOI: https://doi.org/10.64898/2026.01.28.702352
bioRxiv. 2026 Jan 23. pii: 2026.01.22.701190. [Epub ahead of print]

IGF1 peptide targets Rett Syndrome astrocytes to degrade IGF binding protein, rescue synaptogenesis and restore mitochondrial function.

Prachi Ojha, Velina Kozareva, Alexandria Barlowe, Fabian Schulte, Ruby Minh Lam, Danielle L Tomasello, Ernest Fraenkel, Rudolf Jaenisch, Mriganka Sur.

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in MECP2, leads to profound synaptic and circuit deficits in the brain. While neurons have historically been the focus of RTT pathology, emerging evidence implicates astrocytes in non-cell autonomous mechanisms that impair synaptic structure, function and development. Here, we uncover a central role for astrocyte-secreted IGFBP2 in mediating these deficits and demonstrate that treatment with an IGF1-derived peptide restores synapse formation by promoting IGFBP2 degradation. Using an indirect astrocyte-neuron co-culture system, we show that astrocytes derived from RTT model mice suppress excitatory synapse formation in wild-type neurons and that this impairment is reversed when RTT astrocytes are treated with IGF1(1-3) peptide. Proteomic analysis reveals elevated levels of IGFBP2 in RTT astrocytes and their conditioned media. IGF1(1-3) peptide treatment leads to proteasomal degradation of IGFBP2, increasing IGF1 bioavailability, restoring mitochondrial function, and enhancing downstream PI3K/Akt signaling in neurons. Our data define a molecular mechanism by which astrocyte dysfunction in RTT can be rescued and provide a mechanistic basis for the therapeutic efficacy of IGF1(1-3) peptide, including Trofinetide, an FDA-approved IGF1 peptide mimetic, in RTT.
Significance Statement: Astrocyte dysfunction is increasingly recognized as a contributor to neurodevelopmental disorders, yet precise mechanisms remain elusive. Here, we identify IGFBP2 as a key astrocyte-derived inhibitor of synaptogenesis in Rett syndrome. We show that an IGF1-derived peptide, IGF1(1-3), depletes IGFBP2 via proteasomal degradation. This restores IGF1 bioavailability and rescues synaptic function in a non-cell-autonomous manner. These findings provide a mechanistic explanation for the clinical efficacy of IGF1 peptide and its mimetics in Rett syndrome, and highlight astrocytes as rational therapeutic targets in neurodevelopmental and other disorders.

DOI: https://doi.org/10.64898/2026.01.22.701190