Jordan M. Ross

Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics.

Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimers 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 7months. 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 (r(2)=.959), but uncorrelated in transgenics (r(2)=.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.

Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy

BACKGROUNDnMultimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs.nnnMETHODSnAnalyses included 2779 patients with a primary CNS tumor treated at St Jude Childrens Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study.nnnRESULTSnEighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%-3.9%) at 10 years, and 6.0% (95% CI: 4.6%-7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2-85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2-74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38-1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%-19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44).nnnCONCLUSIONnThe cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential.

Adolescent exposure to cocaine, amphetamine, and methylphenidate cross-sensitizes adults to methamphetamine with drug- and sex-specific effects.

The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood.

Minimally invasive highly precise monitoring of respiratory rhythm in the mouse using an epithelial temperature probe.

BACKGROUNDnRespiration 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.nnnNEW METHODnThis 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.nnnRESULTSnWe 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.nnnCOMPARISON WITH EXISTING METHODSnCurrent 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.nnnCONCLUSIONSnHere, 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.

Learning-dependent and —independent enhancement of mitral/tufted cell glomerular odor responses following olfactory fear conditioning in awake mice

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, in vivo 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. SIGNIFICANCE STATEMENT 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.

Olfactory bulb acetylcholine release dishabituates odor responses and reinstates odor investigation

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.Habituation reduces neural responsiveness to prolonged irrelevant stimuli and dishabituation reverses these effects when a salient stimulus is encountered. Here the authors demonstrate that acetylcholine is involved in dishabituating odor responses in the mouse olfactory bulb.

Aversive learning-induced plasticity throughout the adult mammalian olfactory system: insights across development

Experiences, such as sensory learning, are known to induce plasticity in mammalian sensory systems. In recent years aversive olfactory learning-induced plasticity has been identified at all stages of the adult olfactory pathway; however, the underlying mechanisms have yet to be identified. Much of the work regarding mechanisms of olfactory associative learning comes from neonates, a time point before which the brain or olfactory system is fully developed. In addition, pups and adults often express different behavioral outcomes when subjected to the same olfactory aversive conditioning paradigm, making it difficult to directly attribute pup mechanisms of plasticity to adults. Despite the differences, there is evidence of similarities between pups and adults in terms of learning-induced changes in the olfactory system, suggesting at least some conserved mechanisms. Identifying these conserved mechanisms of plasticity would dramatically increase our understanding of how the brain is able to alter encoding and consolidation of salient olfactory information even at the earliest stages following aversive learning. The focus of this review is to systematically examine literature regarding olfactory associative learning across developmental stages and search for similarities in order to build testable hypotheses that will inform future studies of aversive learning-induced sensory plasticity in adults.

Olfactory fear conditioning non-specifically enhances glomerular odor responses and increases representational overlap of learned and neutral odors

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 mice to a classical olfactory fear conditioning paradigm and used awake, in vivo calcium imaging to quantify learning-induced changes in glomerular odor responses, which constitutes the first site of olfactory processing in the brain. The results demonstrate that olfactory fear learning non-specifically enhances glomerular odor representations in a learning-dependent manner and increases representational similarity between the CS and non-conditioned odors. This mechanism may prime the system towards generalization of learned fear. Additionally, CS-specific enhancements remain even when associative learning is blocked; suggesting two separate mechanisms lead to enhanced glomerular responses following odor-shock pairings.