Associative fear learning produces fear toward the conditioned stimulus (CS) and often generalization, the expansion of fear from the CS to similar, unlearned stimuli. However, how fear learning affects early sensory processing of learned and unlearned stimuli in relation to behavioral fear responses to these stimuli remains unclear. We subjected male and female mice expressing the fluorescent calcium indicator GCaMP3 in olfactory bulb mitral and tufted cells to a classical olfactory fear conditioning paradigm. We then used awake, calcium imaging to quantify learning-induced changes in glomerular odor responses, which constitute the first site of olfactory processing in the brain. The results demonstrate that odor-shock pairing nonspecifically enhances glomerular odor representations in a learning-dependent manner and increases representational similarity between the CS and nonconditioned odors, potentially priming the system toward generalization of learned fear. Additionally, CS-specific glomerular enhancements remain even when associative learning is blocked, suggesting two separate mechanisms lead to enhanced glomerular responses following odor-shock pairings. In the olfactory bulb (OB), odors are uniquely coded in a spatial map that represents odor identity, making the OB a unique model system for investigating how learned fear alters sensory processing. Classical fear conditioning causes fear of the conditioned stimulus (CS) and of neutral stimuli, known as generalization. Combining fear conditioning with fluorescent calcium imaging of OB glomeruli, we found enhanced glomerular responses of the CS as well as neutral stimuli in awake mice, which mirrors fear generalization. We report that CS and neutral stimuli enhancements are, respectively, learning-independent and learning-dependent. Together, these results reveal distinct mechanisms leading to enhanced OB processing of fear-inducing stimuli and provide important implications for altered sensory processing in fear generalization.
Habituation and dishabituation modulate the neural resources and behavioral significance allocated to incoming stimuli across the sensory systems. We characterize these processes in the mouse olfactory bulb (OB) and uncover a role for OB acetylcholine (ACh) in physiological and behavioral olfactory dishabituation. We use calcium imaging in both awake and anesthetized mice to determine the time course and magnitude of OB glomerular habituation during a prolonged odor presentation. In addition, we develop a novel behavioral investigation paradigm to determine how prolonged odor input affects odor salience. We find that manipulating OB ACh release during prolonged odor presentations using electrical or optogenetic stimulation rapidly modulates habituated glomerular odor responses and odor salience, causing mice to suddenly investigate a previously ignored odor. To demonstrate the ethological validity of this effect, we show that changing the visual context can lead to dishabituation of odor investigation behavior, which is blocked by cholinergic antagonists in the OB.
Background Respiration is one of the essential rhythms of life. The precise measurement of respiratory behavior is of great importance in studies addressing olfactory sensory processing or the coordination of orofacial movements with respiration. An ideal method of measurement should reliably capture the distinct phases of respiration without interfering with behavior. New Method This new method involves chronic implantation of a thermistor probe in a previously undescribed hollow space located above the anterior portion of the nasal cavity without penetrating any soft epithelial tissues. Results We demonstrate the reliability and precision of the method in head-fixed and freely moving mice by directly comparing recorded signals with simultaneous measurements of chest movements and plethysmographic measurements of respiration. Comparison with Existing Methods Current methods have drawbacks in that they are either inaccurate or require invasive placement of temperature or pressure sensors into the sensitive nasal cavity, where they interfere with airflow and cause irritation and damage to the nasal epithelium. Furthermore, surgical placement within the posterior nasal cavity adjacent to the nasal epithelium requires extensive recovery time, which is not necessary with the described method. Conclusions Here, we describe a new method for recording the rhythm of respiration in awake mice with high precision, without damaging or irritating the nasal epithelium. This method will be effective for measurement of respiration during experiments requiring free movement, as well as those involving imaging or electrophysiology.
Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer’s disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7 months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r2 = .959), but uncorrelated in transgenics (r2 = .013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics’ deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.
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