Biology subjects

Karnani, M. M.

Publications and source records attributed to Karnani, M. M..

6 recordsLinked to original sources

bioRxiv2025

The anterior cingulate cortex drives lateralized age-dependent modulation of claustrum circuits

The anterior cingulate cortex (ACC) sends top-down inputs to the claustrum during sensory, motor, and cognitive processing. This ACC input is thought to drive the activation of claustrum neurons which in turn project back to the cortex to help orchestrate cortical networks during demanding cognitive states such as attention. However, the circuit mechanisms underlying ACC-claustrum signaling are not fully understood. Using in vivo single neuron recordings in mice, we show that ACC neuron activation drives a lateralized modulation of claustrum excitability that changes as a function of postnatal age. In adulthood, ACC activation evoked feed-forward inhibition of ipsilateral excitatory claustrum neurons and activation of contralateral excitatory claustrum neurons. Chemogenetic manipulation in adult mice revealed that ipsilateral claustrum inhibition by the ACC was due to feed-forward activation of claustrum parvalbumin inhibitory neurons. However, in neonatal mice, which lack mature parvalbumin interneurons, ACC inputs evoked claustrum excitation. In juvenile mice, the developmental switch from ACC-evoked claustrum excitation to inhibition occurred in parallel with the maturation of claustrum parvalbumin interneurons, thus corroborating the chemogenetic findings. Therefore, this work provides a novel mechanism of cortical control over claustrum activity that is refined during early postnatal life.

neuroscience↗

bioRxiv2024

Integration of cortical inputs in the lateral hypothalamus is dominated by the medial prefrontal cortex

The lateral hypothalamus (LH) is a critical brain region orchestrating survival behaviours including feeding. Its sparse intrinsic synaptic connectivity allows long-range projections to modulate its activity. Some of these projections arise from the cerebral cortex, which is known to influence feeding. However, the functional and anatomical organization of cortico-hypothalamic pathways have remained poorly studied. We used anatomical and optogenetic mapping to show that the medial prefrontal cortex (mPFC) is the strongest cortical input source to the LH, followed by a lateral associative region including the insular cortex (IC), and the ventral subiculum. Input from the mPFC and IC had markedly different synaptic dynamics and were integrated supralinearly. IC input surpassed that of the mPFC in a subpopulation of highly excitable dorsal LH neurons which had a strong h-current. Input from the mPFC showed selective targeting to LH neurons which project back to the mPFC, suggesting the existence of a direct feedback loop. Overall, these results identify a direct prefrontal hypothalamic pathway which is poised to dominate rapid cortical control of hypothalamic activity.

neuroscience↗

bioRxiv2024

The Switchmaze: an open-design device for measuring motivation and drive switching in mice

Animals need to switch between motivated behaviours, like drinking, feeding or social interaction, to meet environmental availability, internal needs and more complex ethological needs such as hiding future actions from competitors. Inflexible, repetitive behaviours are a hallmark of many neuropsychiatric disorders. However, how the brain orchestrates switching between the neural mechanisms controlling motivated behaviours, or drives, is unknown. This is partly due to a lack of appropriate measurement systems. We designed an automated extended home-cage, the Switchmaze, using open-source hardware and software. In this study, we use it to establish a behavioural assay of motivational switching in mice. Individual animals access the Switchmaze from the home-cage and choose between entering one of two chambers containing different goal objects or returning to the home-cage. Motivational switching is measured as a ratio of switching between chambers and continuous exploitation of one chamber. Behavioural transition analysis is used to further dissect altered motivational switching. As proof-of-concept, we show environmental manipulation, and targeted brain manipulation experiments which altered motivational switching without effect on traditional behavioural parameters. Chemogenetic inhibition of the prefrontal-hypothalamic axis increased the rate of motivation switching, highlighting the involvement of this pathway in drive switching. This work demonstrates the utility of open-design in understanding animal behaviour and its neural correlates.

neuroscience↗

bioRxiv2022

Arousal neurons that anticipate deviations in blood glucose.

Blood glucose variability shapes human brain performance and diverse clinical outcomes. However, it remains poorly understood how blood glucose fluctuations are decoded by genetically-defined neurons to change brain activity and behavior. Recent breakthroughs in genetics and clinical diagnostics identified hypothalamic hypocretin/orexin neurons (HONs) as core determinants of brain activity and adaptive behavior across mammals. Here we show that low-frequency HON population waves are tuned for transmitting information about minute-to-minute temporal features of blood glucose, thus rapidly converting its variability into brain state of behaving mice. Contrary to current theories envisioning glucose-proportional neural responses, the HONs response tracked blood glucose gradients, thus generating efficient neural adaptations in anticipation of maximal glucose deviations. Resolving this population response at the single cell level with volumetric multiphoton imaging furthermore revealed glucose-excited and glucose-inhibited HONs, distinctly coupled to body movements in the high-frequency domain. Finally, HON-selective opotogenetics and cell ablation demonstrated that HONs are critical for linking glucose to adaptive behavior. These results provide an insight into how behaviorally influential hypothalamic networks interpret blood glucose variability. This may inform future metrics for efficient prediction of glycemic states in health and disease.

neuroscience↗

bioRxiv2020

Ultra-sparse connectivity within the lateral hypothalamus

The lateral hypothalamus (LH) contains neuronal populations which generate fundamental behavioural actions such as feeding, sleep, movement, attack and evasion. Their activity is also correlated with various appetitive and consummatory behaviours as well as reward seeking. It is unknown how neural activity within and among these populations is coordinated. One hypothesis postulates that they communicate using inhibitory and excitatory synapses, forming local microcircuits. We inspected this hypothesis using quadruple whole cell recordings and optogenetics to screen thousands of potential connections in brain slices. In contrast to the neocortex, we found near zero connectivity within the LH. In line with its ultra-sparse intrinsic connectivity, we found that the LH does not generate local beta and gamma oscillations. This suggests that LH neurons integrate incoming input within individual neurons rather than through local network interactions, and that input from other brain structures is decisive for selecting active populations in LH.

neuroscience↗

bioRxiv2019

Rapid sensory integration in orexin neurons governs probability of future movements

Internally and externally triggered movement is crucial for survival and is controlled by multiple interconnected neuronal populations spanning many brain areas. Lateral hypothalamic orexin/hypocretin neurons are thought to play a slow, modulatory part in this scheme through their key role in promoting metabolism and wakefulness. However, it is unknown whether orexin/hypocretin neurons participate in rapid neural processing, leading to immediate movement. Furthermore, their role in sensorimotor transformations remains unknown. Here we use cellular-resolution Ca2+ imaging and optogenetics to show that orexin/hypocretin cells are instantaneous regulators of self-generated and sensory-evoked movement. They are activated before and during movement, preventing this activation reduces self-generated locomotion, and optogenetic mimicry of this transient activation rapidly initiates locomotion. We find that the same orexin neurons whose activity predicts movement initiation are rapidly controllable by external sensory stimuli, and silencing orexin cells during sensation prevents normal motor performance. These findings place orexin neurons in a physiological position of unexpectedly rapid and strong sensorimotor control.

neuroscience↗