Richard G. Dickson, Matthew W. Jacobs, John M. Ratliff, Alec L. R. Soronow, Faye An, Walid A. Yuqob, Euiseok J. Kim
Feedforward (FF) and feedback (FB) cortico-cortical neurons are distinct yet spatially intermingled subtypes distributed across cortical layers, playing specialized roles in sensory and cognitive processing. However, whether their presynaptic inputs differ to support these functions remains unknown. Using projection- and layer-specific monosynaptic rabies tracing, we mapped brain-wide long-distance inputs to multiple FF and FB neuron types in VISl (also known as LM), the mouse secondary visual cortex. Overall, long-distance input patterns for these FF and FB neurons were largely similar, as all received the majority of their inputs from VISp, the primary visual cortex, along with substantial inputs from various other cortical and visual thalamic regions. Despite their similarities, these FF and FB types differed in the proportion of long-distance cortical inputs originating from specific visual, retrosplenial, and auditory cortices. These findings reveal the input connectivity patterns of cortico-cortical neurons based on FF and FB projections, providing an anatomical framework for future studies on their functions and circuit integration.
{"title":"Brain-Wide Connectivity Patterns of Feedforward and Feedback Cortico-Cortical Neurons in the Mouse Secondary Visual Cortex","authors":"Richard G. Dickson, Matthew W. Jacobs, John M. Ratliff, Alec L. R. Soronow, Faye An, Walid A. Yuqob, Euiseok J. Kim","doi":"10.1002/cne.70111","DOIUrl":"10.1002/cne.70111","url":null,"abstract":"<p>Feedforward (FF) and feedback (FB) cortico-cortical neurons are distinct yet spatially intermingled subtypes distributed across cortical layers, playing specialized roles in sensory and cognitive processing. However, whether their presynaptic inputs differ to support these functions remains unknown. Using projection- and layer-specific monosynaptic rabies tracing, we mapped brain-wide long-distance inputs to multiple FF and FB neuron types in VISl (also known as LM), the mouse secondary visual cortex. Overall, long-distance input patterns for these FF and FB neurons were largely similar, as all received the majority of their inputs from VISp, the primary visual cortex, along with substantial inputs from various other cortical and visual thalamic regions. Despite their similarities, these FF and FB types differed in the proportion of long-distance cortical inputs originating from specific visual, retrosplenial, and auditory cortices. These findings reveal the input connectivity patterns of cortico-cortical neurons based on FF and FB projections, providing an anatomical framework for future studies on their functions and circuit integration.</p>","PeriodicalId":15552,"journal":{"name":"Journal of Comparative Neurology","volume":"533 12","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cne.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Straus, Anja Ranohavimparany, Nelina Ramanantsoa, Lysandre Tremoureux, Maxime Patout, Marie-Noëlle Fiamma, Florence Cayetanot, Boris Matrot, Jorge Gallego, Laurence Bodineau, Thomas Similowski
Breathing is inherently variable due to the nonlinear dynamics of its brainstem neural control. In amphibians, a gill and a lung oscillator interact to produce breathing but the lung oscillator is necessary and sufficient to produce a mathematically complex behavior. In mammals, where the preBötzinger complex (preBötC) is considered homologous to the amphibian lung oscillator and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) homologous to the amphibian gill oscillator, the origin of ventilatory complexity is not known. We address this question by characterizing ventilation variability in Phox2b mutant mice lacking the RTN/pFRG and human patients with Phox2b mutation-confirmed congenital central hypoventilation syndrome (CCHS). Ventilatory recordings were obtained from Phox2b27ala/+—dying within hours after birth—and Egr2cre/+; Phox2b27ala/+ mice—generally surviving until adulthood—and their wild-type (WT) littermates, during behavioral quiescence at various developmental stages. Human data were collected from CCHS patients and healthy controls during quiet wakefulness. Variability was assessed using the coefficient of variation, complexity using noise titration (noise limit, NL), and sensitivity to initial conditions using the largest Lyapunov exponent (LLE). Mice from both mutant lineages exhibited greater variability at early developmental stages, which decreased with maturation in Egr2cre/+; Phox2b27ala/+ mice. NL was consistently higher in mutant mice than in WT, indicating preserved or even enhanced ventilatory complexity despite RTN/pFRG dysfunction. CO2 reduced variability but did not affect complexity. In humans, no differences were observed between patients and controls for variability, NL, or LLE. Ventilatory complexity persists in mice lacking a functional RTN/pFRG and despite Phox2b mutations in humans, suggesting that the pontomedullary rhythm and pattern generators that include the preBötC may be its principal source. This supports the analogy between mammalian and amphibian rhythm generators.
{"title":"Ventilatory Complexity Persists in Phox2b Mutant Mice Lacking the Retrotrapezoid Nucleus/Parafacial Respiratory Group (RTN/pFRG) and in Humans With Congenital Central Hypoventilation Syndrome","authors":"Christian Straus, Anja Ranohavimparany, Nelina Ramanantsoa, Lysandre Tremoureux, Maxime Patout, Marie-Noëlle Fiamma, Florence Cayetanot, Boris Matrot, Jorge Gallego, Laurence Bodineau, Thomas Similowski","doi":"10.1002/cne.70117","DOIUrl":"10.1002/cne.70117","url":null,"abstract":"<p>Breathing is inherently variable due to the nonlinear dynamics of its brainstem neural control. In amphibians, a gill and a lung oscillator interact to produce breathing but the lung oscillator is necessary and sufficient to produce a mathematically complex behavior. In mammals, where the preBötzinger complex (preBötC) is considered homologous to the amphibian lung oscillator and the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) homologous to the amphibian gill oscillator, the origin of ventilatory complexity is not known. We address this question by characterizing ventilation variability in <i>Phox2b</i> mutant mice lacking the RTN/pFRG and human patients with <i>Phox2b</i> mutation-confirmed congenital central hypoventilation syndrome (CCHS). Ventilatory recordings were obtained from <i>Phox2b</i><sup>27</sup><i><sup>ala/+</sup></i>—dying within hours after birth—and <i>Egr2<sup>cre/+</sup></i>; <i>Phox2b<sup>27ala/+</sup></i> mice—generally surviving until adulthood—and their wild-type (WT) littermates, during behavioral quiescence at various developmental stages. Human data were collected from CCHS patients and healthy controls during quiet wakefulness. Variability was assessed using the coefficient of variation, complexity using noise titration (noise limit, NL), and sensitivity to initial conditions using the largest Lyapunov exponent (LLE). Mice from both mutant lineages exhibited greater variability at early developmental stages, which decreased with maturation in <i>Egr2<sup>cre</sup></i><sup>/+</sup>; <i>Phox2b<sup>27ala/+</sup></i> mice. NL was consistently higher in mutant mice than in WT, indicating preserved or even enhanced ventilatory complexity despite RTN/pFRG dysfunction. CO<sub>2</sub> reduced variability but did not affect complexity. In humans, no differences were observed between patients and controls for variability, NL, or LLE. Ventilatory complexity persists in mice lacking a functional RTN/pFRG and despite <i>Phox2b</i> mutations in humans, suggesting that the pontomedullary rhythm and pattern generators that include the preBötC may be its principal source. This supports the analogy between mammalian and amphibian rhythm generators.</p>","PeriodicalId":15552,"journal":{"name":"Journal of Comparative Neurology","volume":"533 12","pages":""},"PeriodicalIF":2.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Justin Peterle, Kathrin Deborah Wicke, Christina Pätz-Warncke, Felix Felmy
The acoustic startle reaction is a rapid behavioral response to an unexpected auditory stimulus. In mammals, this reaction is based on an archaic reflex arch connecting auditory inputs via the sensor-motor interface in the caudal pontine reticular nucleus (PnC) of the reticular formation with motor output. The neuronal population in the PnC is heterogeneous, containing an interspersed set of giant neurons that represent the cellular substrate of the sensorimotor interface. To probe whether the heterogeneous cell population can be divided into distinct subpopulations based on somatic morphometry or potassium channel expression, we quantitatively analyzed immunofluorescence labeling in the PnC and compared this between three mammals. In gerbil, mouse, and Etruscan shrew, soma size and roundness showed a continuum over all analyzed cells. Somatic Kv1.1 labeling intensity continuously increased with increasing soma size. Overall, no subpopulations based on somatic morphometric parameters and Kv1.1 expression were observed, suggesting that the PnC is composed of neurons displaying a continuum of soma sizes. Moreover, in mice, neurons of the MNTB but not PnC showed a postnatal developmentally regulated Kv1.1 expression, contrasting this sensorimotor interface with the sensory nuclei of the auditory brainstem.
{"title":"In the Caudal Pontine Reticular Nucleus, Kv1.1 Expression Is Soma Size Dependent and Invariant During Postnatal Development.","authors":"Justin Peterle, Kathrin Deborah Wicke, Christina Pätz-Warncke, Felix Felmy","doi":"10.1002/cne.70119","DOIUrl":"10.1002/cne.70119","url":null,"abstract":"<p><p>The acoustic startle reaction is a rapid behavioral response to an unexpected auditory stimulus. In mammals, this reaction is based on an archaic reflex arch connecting auditory inputs via the sensor-motor interface in the caudal pontine reticular nucleus (PnC) of the reticular formation with motor output. The neuronal population in the PnC is heterogeneous, containing an interspersed set of giant neurons that represent the cellular substrate of the sensorimotor interface. To probe whether the heterogeneous cell population can be divided into distinct subpopulations based on somatic morphometry or potassium channel expression, we quantitatively analyzed immunofluorescence labeling in the PnC and compared this between three mammals. In gerbil, mouse, and Etruscan shrew, soma size and roundness showed a continuum over all analyzed cells. Somatic Kv1.1 labeling intensity continuously increased with increasing soma size. Overall, no subpopulations based on somatic morphometric parameters and Kv1.1 expression were observed, suggesting that the PnC is composed of neurons displaying a continuum of soma sizes. Moreover, in mice, neurons of the MNTB but not PnC showed a postnatal developmentally regulated Kv1.1 expression, contrasting this sensorimotor interface with the sensory nuclei of the auditory brainstem.</p>","PeriodicalId":15552,"journal":{"name":"Journal of Comparative Neurology","volume":"533 12","pages":"e70119"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145756846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeffrey G Mellott, Lena M Dellaria, Madeline Guy, Sean R Hergenrother, Nick J Tokar, Dakota Z Smallridge, Miljan Terzic, Jesse W Young, Christine M Dengler-Crish
Numerous studies support a mechanistic link between hearing loss and increased risks of cognitive decline and dementia. Hearing loss is widely viewed as a modifiable risk factor for Alzheimer's disease (AD). During normal aging the inferior colliculus (IC), a large auditory midbrain nucleus, undergoes numerous changes to neurotransmission, and these changes contribute to the development of central gain and presbycusis. Recent reports also implicate the IC as a nucleus that undergoes processing changes during AD. We used transmission electron microscopy (EM) to examine the synaptic ultrastructure of the central IC (ICc) in 3xTG mice during presymptomatic, emerging, and established disease stages. Synapses were identified by a collection of presynaptic vesicles, a clear synaptic cleft, and a postsynaptic density. Symmetric synapses had pre and postsynaptic membranes of similar thickness, whereas asymmetric synapses had postsynaptic densities were conspicuously thicker than the presynaptic densities. We also quantified the presynaptic profile areas, active zone lengths, and presynaptic mitochondria. The data demonstrate a significant loss of symmetric and asymmetric synapses in the emerging disease stage. In particular, the density of symmetric synapses in the ICc was reduced by ∼50%. As inhibitory neurotransmitters gamma-aminobutyric acid (GABA), glycine, and neuropeptide Y are released from neurons that form symmetric synapses in the IC, the robust loss of these synapses may contribute to central gain and presbycusis during AD. Furthermore, as these synapses were lost well before the established disease stages, perhaps alterations in ICc represent an early biomarker for Alzheimer's progression.
{"title":"Ultrastructural Synaptic Differences in the Central Inferior Colliculus in the 3xTG Mouse Across Three Disease Stages.","authors":"Jeffrey G Mellott, Lena M Dellaria, Madeline Guy, Sean R Hergenrother, Nick J Tokar, Dakota Z Smallridge, Miljan Terzic, Jesse W Young, Christine M Dengler-Crish","doi":"10.1002/cne.70120","DOIUrl":"10.1002/cne.70120","url":null,"abstract":"<p><p>Numerous studies support a mechanistic link between hearing loss and increased risks of cognitive decline and dementia. Hearing loss is widely viewed as a modifiable risk factor for Alzheimer's disease (AD). During normal aging the inferior colliculus (IC), a large auditory midbrain nucleus, undergoes numerous changes to neurotransmission, and these changes contribute to the development of central gain and presbycusis. Recent reports also implicate the IC as a nucleus that undergoes processing changes during AD. We used transmission electron microscopy (EM) to examine the synaptic ultrastructure of the central IC (ICc) in 3xTG mice during presymptomatic, emerging, and established disease stages. Synapses were identified by a collection of presynaptic vesicles, a clear synaptic cleft, and a postsynaptic density. Symmetric synapses had pre and postsynaptic membranes of similar thickness, whereas asymmetric synapses had postsynaptic densities were conspicuously thicker than the presynaptic densities. We also quantified the presynaptic profile areas, active zone lengths, and presynaptic mitochondria. The data demonstrate a significant loss of symmetric and asymmetric synapses in the emerging disease stage. In particular, the density of symmetric synapses in the ICc was reduced by ∼50%. As inhibitory neurotransmitters gamma-aminobutyric acid (GABA), glycine, and neuropeptide Y are released from neurons that form symmetric synapses in the IC, the robust loss of these synapses may contribute to central gain and presbycusis during AD. Furthermore, as these synapses were lost well before the established disease stages, perhaps alterations in ICc represent an early biomarker for Alzheimer's progression.</p>","PeriodicalId":15552,"journal":{"name":"Journal of Comparative Neurology","volume":"533 12","pages":"e70120"},"PeriodicalIF":2.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12704581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reyansh N. Sathishkumar, Ethan H. Willbrand, Priyanka Nanayakkara, Willa I. Voorhies, Yi-Heng Tsai, Thomas Gagnant, William D. Hopkins, Chet C. Sherwood, Kevin S. Weiner