Body weight, gonadectomy, and other risk factors for diagnosis of osteoarthritis in companion dogs.

Objective: The aim of this study is to evaluate age, sex, body weight, breed, neuter status, and age at neutering as risk factors for diagnosis of osteoarthritis in companion dogs. Animals: Dogs seen as patients at Banfield Pet Hospital in the United States from 1998 to 2019 with a date of death in 2019. The final cohort consisted of 131,140 dogs. Methods: In this retrospective cohort study, Cox proportional hazard models were used to test for associations between osteoarthritis incidence and age at baseline, sex, maximum body weight, maximum body condition score, neuter status, and age at neutering. The same model was used to test these associations in 12 representative breeds, chosen based on breed weight and sample size. Results: Older age, higher adult body weight, gonadectomy, and younger age at gonadectomy were significantly associated with higher risks of osteoarthritis in the total cohort and in all 12 breeds evaluated. Higher body condition scores and sex were also significantly associated with osteoarthritis but with minimal effect sizes in the overall cohort, and these risk factors were not consistently significant in all breeds tested. Clinical relevance: These results will assist veterinarians in identifying dogs at higher risk for osteoarthritis and applying appropriate diagnostic, preventative, and treatment interventions. An understanding of potentially modifiable risk factors, such as body condition and neutering, will support evidence-based discussions with dog owners about risk management in individual patients.

Evaluating instruments for assessing healthspan: a multi-center cross-sectional study on health-related quality of life (HRQL) and frailty in the companion dog.

Developing valid tools that assess key determinants of canine healthspan such as frailty and health-related quality of life (HRQL) is essential to characterizing and understanding aging in dogs. Additionally, because the companion dog is an excellent translational model for humans, such tools can be applied to evaluate gerotherapeutics and investigate mechanisms underlying longevity in both dogs and humans. In this multi-center, cross-sectional study, we investigated the use of a clinical questionnaire (Canine Frailty Index; CFI; Banzato et al., 2019) to assess frailty and an owner assessment tool (VetMetrica HRQL) to evaluate HRQL in 451 adult companion dogs. Results demonstrated validity of the tools by confirming expectations that frailty score increases and HRQL scores deteriorate with age. CFI scores were significantly higher (higher frailty) and HRQL scores significantly lower (worse HRQL) in old dogs (≥ 7 years of age) compared to young dogs (≥ 2 and < 6 years of age). Body size (small < 11.3 kg (25 lbs) or large > 22.7 kg (50 lbs)) was not associated with CFI or total HRQL score. However, older, larger dogs showed faster age-related decline in HRQL scores specific to owner-reported activity and comfort. Findings suggest that the clinician-assessed CFI and owner-reported VetMetrica HRQL are useful tools to evaluate two determinants of healthspan in dogs: the accumulation of frailty and the progressive decline in quality of life. Establishing tools that operationalize the assessment of canine healthspan is critical for the advancement of geroscience and the development of gerotherapeutics that benefit both human and veterinary medicine. Graphical summary of the design, results, and conclusions of the study.

Complementary networks of cortical somatostatin interneurons enforce layer specific control.

The neocortex is functionally organized into layers. Layer four receives the densest bottom up sensory inputs, while layers 2/3 and 5 receive top down inputs that may convey predictive information. A subset of cortical somatostatin (SST) neurons, the Martinotti cells, gate top down input by inhibiting the apical dendrites of pyramidal cells in layers 2/3 and 5, but it is unknown whether an analogous inhibitory mechanism controls activity in layer 4. Using high precision circuit mapping, in vivo optogenetic perturbations, and single cell transcriptional profiling, we reveal complementary circuits in the mouse barrel cortex involving genetically distinct SST subtypes that specifically and reciprocally interconnect with excitatory cells in different layers: Martinotti cells connect with layers 2/3 and 5, whereas non-Martinotti cells connect with layer 4. By enforcing layer-specific inhibition, these parallel SST subnetworks could independently regulate the balance between bottom up and top down input.

Superficial Layers Suppress the Deep Layers to Fine-tune Cortical Coding.

The descending microcircuit from layer 2/3 (L2/3) to layer 5 (L5) is one of the strongest excitatory pathways in the cortex, presumably forming a core component of its feedforward hierarchy. To date, however, no experiments have selectively tested the impact of L2/3 activity on L5 during active sensation. We used optogenetic, cell-type-specific manipulation of L2/3 neurons in the barrel cortex of actively sensing mice (of either sex) to elucidate the significance of this pathway to sensory coding in L5. Contrary to standard models, activating L2/3 predominantly suppressed spontaneous activity in L5, whereas deactivating L2/3 mainly facilitated touch responses in L5. Somatostatin interneurons are likely important to this suppression because their optogenetic deactivation significantly altered the functional impact of L2/3 onto L5. The net effect of L2/3 was to enhance the stimulus selectivity and expand the range of L5 output. These data imply that the core cortical pathway increases the selectivity and expands the range of cortical output through feedforward inhibition.SIGNIFICANCE STATEMENT The primary sensory cortex contains six distinct layers that interact to form the basis of our perception. While rudimentary patterns of connectivity between the layers have been outlined quite extensively in vitro, functional relationships in vivo, particularly during active sensation, remain poorly understood. We used cell-type-specific optogenetics to test the functional relationship between layer 2/3 and layer 5. Surprisingly, we discovered that L2/3 primarily suppresses cortical output from L5. The recruitment of somatostatin-positive interneurons is likely fundamental to this relationship. The net effect of this translaminar suppression is to enhance the selectivity and expand the range of receptive fields, therefore potentially sharpening the perception of space.

Cracking the Function of Layers in the Sensory Cortex.

Understanding how cortical activity generates sensory perceptions requires a detailed dissection of the function of cortical layers. Despite our relatively extensive knowledge of their anatomy and wiring, we have a limited grasp of what each layer contributes to cortical computation. We need to develop a theory of cortical function that is rooted solidly in each layer's component cell types and fine circuit architecture and produces predictions that can be validated by specific perturbations. Here we briefly review the progress toward such a theory and suggest an experimental road map toward this goal. We discuss new methods for the all-optical interrogation of cortical layers, for correlating in vivo function with precise identification of transcriptional cell type, and for mapping local and long-range activity in vivo with synaptic resolution. The new technologies that can crack the function of cortical layers are finally on the immediate horizon.

Inhibitory Circuits in Cortical Layer 5.

Inhibitory neurons play a fundamental role in cortical computation and behavior. Recent technological advances, such as two photon imaging, targeted in vivo recording, and molecular profiling, have improved our understanding of the function and diversity of cortical interneurons, but for technical reasons most work has been directed towards inhibitory neurons in the superficial cortical layers. Here we review current knowledge specifically on layer 5 (L5) inhibitory microcircuits, which play a critical role in controlling cortical output. We focus on recent work from the well-studied rodent barrel cortex, but also draw on evidence from studies in primary visual cortex and other cortical areas. The diversity of both deep inhibitory neurons and their pyramidal cell targets make this a challenging but essential area of study in cortical computation and sensory processing.

Barrels XXVIII take the Windy City by storm.

The 28th annual Barrels meeting was held prior to the Society for Neuroscience meeting in October 2015 at the Northwestern University School of Law in Chicago, Illinois. The meeting brought together researchers focused on the rodent sensorimotor system. The meeting focused on modern techniques to decipher cortical circuits, social interactions among rodents, and decision-making. The meeting allowed investigators to share their work via short talks, poster presentations, and a data blitz.

A direct translaminar inhibitory circuit tunes cortical output.

Anatomical and physiological experiments have outlined a blueprint for the feedforward flow of activity in cortical circuits: signals are thought to propagate primarily from the middle cortical layer (layer 4, L4) up to L2/3 and down to the major cortical output layer (L5). Pharmacological manipulations, however, have contested this model and have suggested that L4 may not be critical for sensory responses of neurons in either superficial or deep layers. To address these conflicting models, we reversibly manipulated L4 activity in awake, behaving mice using cell type-specific optogenetics. In contrast with both prevailing models, we found that activity in L4 directly suppressed L5, in part by activating deep, fast-spiking inhibitory neurons. Our data suggest that the net effect of L4 activity is to sharpen the spatial representations of L5 neurons. Thus, we establish a previously unknown translaminar inhibitory circuit in the sensory cortex that acts to enhance the feature selectivity of cortical output.