65 years of research on dopamine's role in classical fear conditioning and extinction: A systematic review.

Dopamine, a catecholamine neurotransmitter, has historically been associated with the encoding of reward, whereas its role in aversion has received less attention. Here, we systematically gathered the vast evidence of the role of dopamine in the simplest forms of aversive learning: classical fear conditioning and extinction. In the past, crude methods were used to augment or inhibit dopamine to study its relationship with fear conditioning and extinction. More advanced techniques such as conditional genetic, chemogenic and optogenetic approaches now provide causal evidence for dopamine's role in these learning processes. Dopamine neurons encode conditioned stimuli during fear conditioning and extinction and convey the signal via activation of D1-4 receptor sites particularly in the amygdala, prefrontal cortex and striatum. The coordinated activation of dopamine receptors allows for the continuous formation, consolidation, retrieval and updating of fear and extinction memory in a dynamic and reciprocal manner. Based on the reviewed literature, we conclude that dopamine is crucial for the encoding of classical fear conditioning and extinction and contributes in a way that is comparable to its role in encoding reward.

Non-invasive Monitoring of α-Synuclein in Saliva for Parkinson's Disease Using Organic Electrolyte-Gated FET Aptasensor.

Parkinson's disease (PD) currently affects more than 1 million people in the US alone, with nearly 8.5 million suffering from the disease worldwide, as per the World Health Organization. However, there remains no fast, pain-free, and effective method of screening for the disease in the ageing population, which also happens to be the most susceptible to this neurodegenerative disease. αSynuclein (αSyn) is a promising PD biomarker, demonstrating clear delineations between levels of the αSyn monomer and the extent of αSyn aggregation in the saliva of PD patients and healthy controls. In this work, we have demonstrated a laboratory prototype of a soft fluidics integrated organic electrolyte-gated field-effect transistor (OEGFET) aptasensor platform capable of quantifying levels of αSyn aggregation in saliva. The aptasensor relies on a recently reported synthetic aptamer which selectively binds to αSyn monomer as the bio-recognition molecule within the integrated fluidic channel of the biosensor. The produced saliva sensor is label-free, fast, and reusable, demonstrating good selectivity only to the target molecule in its monomer form. The novelty of these devices is the fully isolated organic semiconductor, which extends the shelf life, and the novel fully integrated soft microfluidic channels, which simplify saliva loading and testing. The OEGFET aptasensor has a limit of detection of 10 fg/L for the αSyn monomer in spiked saliva supernatant solutions, with a linear range of 100 fg/L to 10 µg/L. The linear range covers the physiological range of the αSyn monomer in the saliva of PD patients. Our biosensors demonstrate a desirably low limit of detection, an extended linear range, and fully integrated microchannels for saliva sample handling, making them a promising platform for non-invasive point-of-care testing of PD.

Preadolescent exposure to a sexually mature, unrelated male rat reduces postadolescent social recognition memory and CA2 c-Fos labeling.

Introduction: Social memory involves social recognition: the ability to discriminate between two or more conspecifics when one has been previously encountered. The CA2 region of the hippocampus has been implicated in social memory, as lesions and dysfunction to this area lead to social memory impairments. A variety of psychogenic manipulations during postnatal sensitive developmental periods are associated with social memory impairments later in life. Methods: In this study, we exposed preadolescent rats to a sexually, mature unrelated male and examined whether this was associated with changes in postadolescent social memory and c-Fos labeling in the CA2 region. Male and female Long-Evans rats were exposed to a male, adult rat on postnatal days 19-21 (P19-21). Social memory was measured during the postadolescent period and defined as increased interactions towards a novel age-matched rat in contrast to a previously-encountered age-matched rat. After the test, rats were euthanized and brain tissue was then collected to quantify c-Fos labeling within the CA2 region. Results: Compared to home cage controls and controls not exposed to the adult male, male and female rats exposed to the unrelated adult during preadolescence were unable to discriminate between a novel and previously encountered conspecific during the postadolescent test showing social memory deficits. The groups that showed social recognition deficits also had significantly fewer c-Fos-positive cells within the CA2 region compared to the control groups. Discussion: These findings indicate that threatening psychogenic encounters during preadolescence can have detrimental long-term effects on social memory potentially via disrupted activity in the CA2 hippocampal region.

Exploring the Connection Between the Gut Microbiome and Parkinson's Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options.

The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson's disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts  100-500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms.

Hyperacute Excitotoxic Mechanisms and Synaptic Dysfunction Involved in Traumatic Brain Injury.

The biological response of brain tissue to biomechanical strain are of fundamental importance in understanding sequela of a brain injury. The time after impact can be broken into four main phases: hyperacute, acute, subacute and chronic. It is crucial to understand the hyperacute neural outcomes from the biomechanical responses that produce traumatic brain injury (TBI) as these often result in the brain becoming sensitized and vulnerable to subsequent TBIs. While the precise physical mechanisms responsible for TBI are still a matter of debate, strain-induced shearing and stretching of neural elements are considered a primary factor in pathology; however, the injury-strain thresholds as well as the earliest onset of identifiable pathologies remain unclear. Dendritic spines are sites along the dendrite where the communication between neurons occurs. These spines are dynamic in their morphology, constantly changing between stubby, thin, filopodia and mushroom depending on the environment and signaling that takes place. Dendritic spines have been shown to react to the excitotoxic conditions that take place after an impact has occurred, with a shift to the excitatory, mushroom phenotype. Glutamate released into the synaptic cleft binds to NMDA and AMPA receptors leading to increased Ca2+ entry resulting in an excitotoxic cascade. If not properly cleared, elevated levels of glutamate within the synaptic cleft will have detrimental consequences on cellular signaling and survival of the pre- and post-synaptic elements. This review will focus on the synaptic changes during the hyperacute phase that occur after a TBI. With repetitive head trauma being linked to devastating medium - and long-term maladaptive neurobehavioral outcomes, including chronic traumatic encephalopathy (CTE), understanding the hyperacute cellular mechanisms can help understand the course of the pathology and the development of effective therapeutics.

Relating strain fields with microtubule changes in porcine cortical sulci following drop impact.

The biomechanical response of brain tissue to strain and the immediate neural outcomes are of fundamental importance in understanding mild traumatic brain injury (mTBI). The sensitivity of neural tissue to dynamic strain events and the resulting strain-induced changes are considered to be a primary factor in injury. Rodent models have been used extensively to investigate impact-induced injury. However, the lissencephalic structure is inconsistent with the human brain, which is gyrencephalic (convoluted structure), and differs considerably in strain field localization effects. Porcine brains have a similar structure to the human brain, containing a similar ratio of white-grey matter and gyrification in the cortex. In this study, coronal brain slabs were extracted from female pig brains within 2hrs of sacrifice. Slabs were implanted with neutral density radiopaque markers, sealed inside an elastomeric encasement, and dropped from 0.9 m onto a steel anvil. Particle tracking revealed elevated tensile strains in the sulcus. One hour after impact, decreased microtubule associated protein 2 (MAP2) was found exclusively within the sulcus with no increase in cell death. These results suggest that elevated tensile strain in the sulcus may result in compromised cytoskeleton, possibly indicating a vulnerability to pathological outcomes under the right circumstances. The results demonstrated that the observed changes were unrelated to shear strain loading of the tissues but were more sensitive to tensile load.

The effects of morphine withdrawal and conditioned withdrawal on memory consolidation and c-Fos expression in the central amygdala.

The current study tested the hypothesis that drug withdrawal contributes to the addiction cycle in part because of an action on memory consolidation. Hence, four experiments in male Sprague-Dawley rats compared the effects of precipitated morphine withdrawal and conditioned morphine withdrawal on the consolidation of object memory and on activation of c-Fos in the central nucleus of the amygdala (CeA). It was found that immediate, but not 6 h delayed, post sample administration of 3 mg/kg of naltrexone significantly enhanced object memory in rats maintained, or previously maintained, on 10 mg/kg/day of morphine via osmotic minipumps. To establish whether conditioned withdrawal could also alter object memory, a contextual conditioning procedure was employed whereby morphine-maintained (10 mg/kg/day) animals received naltrexone (3 mg/kg) in a distinctive context (CS+) and vehicle in a separate context (CS-) for 10 days. During conditioning in the CS+, naltrexone suppressed locomotor activity, caused a rapid body weight loss and increased frequency of wet dog shakes. Interestingly, confinement to this CS+ immediately, but not 6 h, after the sample phase, also enhanced object memory. Finally, posttraining naltrexone and exposure to the CS+ both induced significant expression of c-Fos in the CeA. Therefore, this study reports for the first time that both acute precipitated withdrawal and conditioned withdrawal can facilitate memory consolidation, possibly through a common neural pathway that involves the central amygdala.

Predictors of Concussion Outcomes in Individuals With ADHD.

OBJECTIVES: To describe and delineate the epidemiological profile of concussion injuries in individuals with attention-deficit/hyperactivity disorder (ADHD) by identifying characteristics associated with poorer outcomes. SETTING: One hundred forty-four multidisciplinary concussion-specialized clinics across Canada. PARTICIPANTS: Two hundred twenty-two individuals with a diagnosis of ADHD aged 7 to 53 years who sustained a concussion within the last year. DESIGN: Multicenter cohort study. MAIN MEASURES: Candidate predictor variables (ie, age, sex, concussion history, loss of consciousness, and internalized and learning disorder comorbidities) were collected through oral interviews. Concussion outcomes (ie, symptom severity and total number of symptoms experienced) were assessed with the Sport Concussion Assessment Tool. RESULTS: Older age, female sex, and the presence of an internalized disorder predicted poorer concussion outcomes in individuals with ADHD. Males with ADHD reported significantly worse concussion outcomes with increasing age, while outcomes remained fairly stable across age in females. CONCLUSION: The current findings represent a promising step toward the optimization of concussion management in individuals with ADHD. With a more thorough understanding of the demographic and comorbidity variables, clinical care decisions and intervention strategies can be developed to help individuals with ADHD who might be at a higher risk of poorer outcomes following a concussion.

Hippocampal and anterior cingulate cortex contribution to the processing of recently-acquired and remotely stored spatial memories in rats trained during preadolescence.

Preadolescent development is characterized by a reorganization of connectivity within and between brain regions that coincides with the emergence of more complex behaviors. The hippocampus is one such region that undergoes extensive preadolescent remodeling and as this process continues, spatial memory functions emerge. The current work investigated whether preadolescent spatial memories persist beyond 24 h and stabilize into the postadolescent period as remote memories supported by cortical networks in the anterior cingulate cortex (ACC). Male Long Evans rats were trained on the Morris water maze at different time frames from postnatal day (P) 18-26 and compared to P50 rats. Testing occurred at either a recent (24 h) or remote (3 weeks) timepoint. Spatial learning was evident in all age groups (P18, P20, P22, P24 and P50) across the 3 training days but only the P22 and P24 groups showed spatial learning that matched the P50 group. In light of this, the only group to show intact remote (3 week) memory was the P50 group. Spaced training in the P18 group did not improve retention at the recent or remote testing intervals. The P18 and P50 groups tested at 24 h showed more CA1 hippocampal c-Fos labeling than groups tested at 3 weeks. The P50 group tested at 3 weeks showed elevated c-Fos labeling in the anterior cingulate (ACC) compared to the P18 group tested at 3 weeks and the P50 group tested at 24 h. Spaced training in the P18 group was associated with elevated c-Fos labeling in the ACC at the 3-week test. Groups trained at P20, 22, and 24 showed more c-Fos labelling in the ACC than in the CA1. Results suggest that while spatial information processing emerges around P18/P20, remote spatial retention and the neural substrates that support retention are not in place until after P26 in rats.

Investigation of GluA1 and GluA2 AMPA receptor subtype distribution in the hippocampus and anterior cingulate cortex of Long Evans rats during development.

Preadolescent development is characterized by a reorganization of connectivity within and between brain regions that coincides with the emergence of complex behaviors. During the preadolescent period, the rodent hippocampus and regions of the frontal cortex are remodelled as the brain strengthens active connections and eliminates others. In the developing and mature brain, changes in the properties of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAr)-mediated synaptic responses contribute to experience-dependent changes in neural organization and function. AMPAr are made up of 4 subunits, of which GluA1 and GluA2 have been shown to play the most prominent role in functional plasticity. In this study, we sought to determine whether levels of these two subunits changed during the course of pre-adolescent development in the hippocampus and anterior cingulate cortex (ACC). To investigate the developmental changes in GluA1 and GluA2 AMPAr subunits, Western blotting and immunohistochemistry were performed on the ACC and hippocampus from P18 - P30 and compared to adult (P50) levels and distribution. Within the hippocampus, protein levels of GluA1 and GluA2 peaked around P26-30 whereby localized staining in the dentate gyrus reflected this pattern. GluA1 and GluA2 levels within the ACC showed little variation during this developmental period. These results indicate that changes in AMPAr subunits within the hippocampus coincide with developmental modifications that underlie the shift from juvenile- to adult-like capabilities. However, changes in AMPAr distribution in the ACC might not mediate changes that reflect preadolescent developmental shifts.

Preadolescent dopamine receptor antagonism increases postadolescent reward-related operant behaviors that may depend on dopamine receptor hypersensitivity.

The dopaminergic system has a long history of being associated with reward-related activities but the developmental consequences of blocking dopamine receptor function on reward-based associative learning has been less studied. To this end, male, Long Evans rats were systemically (i.p.) treated with the dopamine receptor (DAr) antagonist, flupenthixol (0.25 mg/kg), or saline, from postnatal day (P)18 - 24 (preadolescence) then trained on an operant conditioning task from P41 - P45 (postadolescent) without drug treatment. The preadolescent flupenthixol group showed elevated active lever responses and locomotor activity during the drug-free test. Another group of rats was given flupenthixol prior to each acquisition session from P41 - 45 which significantly suppressed both active lever presses and locomotor activity. Separate groups of rats were treated with flupenthixol or saline from P18 - 24 then treated with apomorphine or saline on P41 followed by assessment of c-Fos labeling in the nucleus accumbens. Early flupenthixol treatment was associated with more apomorphine-induced c-Fos labeling in the nucleus accumbens shell than the early saline-apomorphine group, indicating a sensitized response. These findings suggest that preadolescent dopamine receptor blockade may lead to a sensitized postadolescent dopaminergic response that underlies enhanced behavioral responses in the presence of rewarding stimuli.

Self-Reported Mild Traumatic Brain Injuries in Relation to Rumination and Depressive Symptoms: Moderating Role of Sex Differences and a Brain-Derived Neurotrophic Factor Gene Polymorphism.

OBJECTIVE: Mild traumatic brain injuries (mTBIs) have frequently been associated with the emergence and persistence of depressive symptoms. However, the factors which contribute to the increased risk for depression after these head injuries remain unclear. Accordingly, we examined the relationship between frequency of self-reported mTBIs and current symptoms of depression and the mediating role of rumination and cognitive flexibility. We also examined whether these relations were moderated by sex differences and the presence of the Val66Met polymorphism in a gene coding for brain-derived neurotrophic factor (BDNF). DESIGN: Retrospective, cross-sectional. SETTING: Carleton University. PARTICIPANTS: Two hundred nineteen Carleton University undergraduate students. MAIN OUTCOME MEASURES: Cognitive flexibility as assessed by the Wisconsin Card Sorting Task (WCST); subtypes of rumination (Ruminative Response Scale; Treynor, Gonzalez, and Nolen-Hoeksema, 2003); depressive symptoms (Beck Depression Inventory; Beck, Ward, and Mendelson, 1961). RESULTS: Greater frequency of self-reported mTBIs was associated with more frequent depressive rumination among women, but not men, which was accompanied by elevated current depressive symptoms. In addition, among Met allele carriers of the BDNF polymorphism, but not those who were Val homozygotes, greater frequency of mTBIs was related to higher levels of brooding, which was accompanied by heightened depressive symptoms. Brain-derived neurotrophic factor genotype also moderated the relationship between self-reported mTBIs and cognitive flexibility in that more frequent mTBIs were associated with more perseverative errors on the WCST among Met carriers, but not Val homozygotes. CONCLUSIONS: The present findings raise the possibility that the evolution of depression after mTBIs may be dependant on a BDNF polymorphism and sex differences.

A systematic review of aerobic and resistance exercise and inflammatory markers in people with multiple sclerosis.

Inflammation is a driver in the demyelination process in patients with multiple sclerosis (MS) and can influence disability levels. Both single and repeated bouts of exercise can decrease inflammatory markers in people with MS (PwMS). This systematic review evaluates whether exercise can influence inflammation and disability in individuals with MS. Experimental studies were reviewed that had to meet the following eligibility requirements: a sample of PwMS, an intervention of exercise (either aerobic, resistance, or a combination of each), and an outcome that included at least one inflammatory (cytokine) reaction. The main outcome measure was an evaluation of inflammation, as indicated by a change in any cytokine level. Other measures included muscle strength, balance, flexibility, walking ability, disability statues, and quality of life (QOL). A total of nine studies were included in the final review. Exercise interventions included predominantly cycling, although a few resistance training trials were mentioned. Small decreases were found in IL-17 and IFN-γ after exercise. Functional outcome measures and perceived disability status were improved posttraining. We conclude that while interventions such as exercise may impact QOL, they do not have a significant influence on inflammation associated with MS. Exercise is an accessible alternative that not only helps to decrease impairments but also limit the restrictions associated with participation in society. While functional outcomes after exercise improved, these improvements may not be attributable to changes in levels of cytokines or inflammatory markers.

Social Memory and the Role of the Hippocampal CA2 Region.

The CA2 region of the hippocampus is a somewhat obscure area lacking in an understanding of its form and function. Until recently, the CA2 has been thought of as merely an extension of the CA3, with some referring to it as the CA3a region. Recent investigations into this area have not only delineated the CA2, but also defined it as a region distinct from both CA1 and CA3, with a unique set of cortical inputs and outputs and contributions to cognitive processes. One such process that has been shown to depend on the CA2 is the ability to recognize a novel or familiar conspecific, known as social recognition memory. Here, we review these findings and discuss the parallels between CA2 dysfunction and social impairments.

Developmental Aspects of Glucose and Calcium Availability on the Persistence of Memory Function Over the Lifespan.

An important aspect concerning the underlying nature of memory function is an understanding of how memories are acquired and lost. The stability, and ultimate demise, of memory over the lifespan of an organism remains a critical topic in determining the neurobiological mechanisms that mediate memory representations. This has important implications for the elucidation and treatment of neurodegenerative diseases such as Alzheimer's disease (AD). One important question in the context of preserving functional plasticity over the lifespan is the determination of the neurobiological structural and functional changes that contribute to the formation of memory during the juvenile time frame that might provide protection against later memory dysfunction by promoting the establishment of redundant neural pathways. The main question being, if memory formation during the juvenile period does strengthen and preserve memory stability over the lifespan, what are the neurobiological structural or functional substrates that mediate this effect? One neural attribute whose function may be altered with early life experience and provide a mechanism to preserve memory through the lifespan is glucose transport-linked calcium (Ca2+) buffering. Because peak increases in glucose utilization overlap with a timeframe during which spatial training can enhance later memory processing, it might be the case that learning-associated changes in glucose utilization would provide an important neural functional change to preserve memory function throughout the lifespan. The glucose transporters are proteins that are reduced in AD pathology and there is evidence that glucose reductions can impair Ca2+ buffering. In the absence of an appropriate supply of ATP, provided via glucose transport and glycolysis, Ca2+ levels can rise leading to neural vulnerability with ensuing pathological outcomes. In this review, we explore the hypothesis that enhancing glucose utilization with spatial training during the preadolescent period will provide a functional enhancement that regulates glucose-dependent Ca2+ signaling during aging or neurodegeneration and provide essential neural resources to preserve functional plasticity and memory function.

Different periods of forced abstinence after instrumental learning for food reward of different macronutrient value on responding for conditioned cues and AMPAr subunit levels.

Food craving can be viewed as an intense desire for a specific food that propagates seeking and consuming behavior. Prolonged forced abstinence from rewarding foods can result in escalated food-seeking behavior as measured via elevated responding for food-paired cues in the absence of the primary reward. Palatable food consumption and food-seeking is associated with changes in the abundance and composition of AMPA receptors in the nucleus accumbens (NAc) but differing results have been reported. The present study examined whether different food types could produce escalated food-seeking behavior after various abstinence periods and whether this was associated with changes in AMPA receptor protein levels. Rats were trained for 10 days to bar press for purified, sucrose, or chocolate-flavored sucrose pellets. Rats were tested at 24 hrs, 7 d or 14 d whereby bar pressing resulted in presentation of cues paired with food but no food reward was delivered. Western blotting was used to determine protein levels of GluR1, GluR1pSer845, and GluR2 in the NAc. Three separate groups were assessed: 1) a group that was trained on the operant task and tested for conditioned responding (tested group); 2) a group that was trained on the operant task but not tested (non-tested group); 3) a group that was neither trained nor tested (control). The purified food group showed a time-dependent elevation in conditioned bar pressing over the 3 abstinence periods. GluR1 AMPAr subunit levels were higher in the purified and sucrose groups tested at 24 hours compared to the non-tested and control values. GluR1 levels subsequently declined at the 7- and 14-day abstinence periods in the purified and sucrose tested and non-tested groups compared to control values. GluR2 and pSer845 Glur1 levels were similar across all groups and abstinence periods. These results show that food-seeking behavior associated with forced abstinence from different food rewards may depend on the macronutrient composition of the food reward or the food type given during the abstinence period. A clear link with AMPAr subunit levels in this model was not established.

The Use of Pigs as a Translational Model for Studying Neurodegenerative Diseases.

In recent years, the move to study neurodegenerative disease using larger animal models with brains that are more similar to humans has gained interest. While pigs have been used for various biomedical applications and research, it has only been recently that they have been used to study neurodegenerative diseases due to their neuroanatomically similar gyrencephalic brains and similar neurophysiological processes as seen in humans. This review focuses on the use of pigs in the study of Alzheimer's disease (AD) and traumatic brain injury (TBI). AD is considered the most common neurodegenerative disease in elderly populations. Head impacts from falls are the most common form of injury in the elderly and recent literature has shown an association between repetitive head impacts and the development of AD. This review summarizes research into the pathological mechanisms underlying AD and TBI as well as the advantages and disadvantages of using pigs in the neuroscientific study of these disease processes. With the lack of successful therapeutics for neurodegenerative diseases, and an increasing elderly population, the use of pigs may provide a better translational model for understanding and treating these diseases.

Interaction between Age, Sex, and Mental Health Status as Precipitating Factors for Symptom Presentation in Concussed Individuals.

Concussions are among the most common neurological conditions, with emergency departments and sports injury clinics seeing hundreds of patients each year. The consideration of risk factors such as age, sex, and comorbid conditions are very important when looking at individual physiological and psychological outcomes after a concussion. The purpose of this study was to look at four comorbid conditions (depression, anxiety, behavioural disorder, or learning disability) and identify any interactions with age and sex in symptom presentation after suffering a concussion. A total of 4,865 participants from the CCMI (Complete Concussion Management Inc.) dataset were used with 1,577 self-identified with a diagnosis of anxiety, depression, a behavioural disorder, or a learning disability. Fixed-factor analyses of variance were used with age and sex as fixed, grouping factors and symptom total and severity as dependent measures. For the individuals who did not have one of the 4 mental health conditions (3,288 control participants), symptom total and symptom severity increased with age (p < 0.05), and females showed more symptoms and a higher symptom severity than males across all ages (p < 0.05). A diagnosis of anxiety or depression exacerbated total symptoms and symptom severity from 25-50% above control levels in the 19 and under age groups, while depression or anxiety exacerbated total symptoms and severity by 10-15% in males more than females over 20. A diagnosis of a behavioural disorder or a learning disability exacerbated symptom severity by approximately 50% above control levels in 13-19-year-old females and in males of 30 years and older. This study highlights how the presence of a mental health condition may alter concussion symptom presentation dependent on age and sex. The identification of risk factors and how they may interact can be of great value to health care providers who manage concussion symptoms and recovery.

In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System To Study Dopamine Dysregulation in the Central Nervous System.

The delivery of therapeutics across the blood-brain barrier remains a considerable challenge in investigating central nervous system related processes. In this work, a liposome vehicle was surface-modified with an aptamer that binds to the transferrin receptor and was loaded with two different dopamine-binding aptamer payloads. This system was effectively used to promote the delivery of the aptamer cargo from the peripheral injection site into the brain. The effect of these delivered aptamers on behavior was investigated in vivo in a locomotor task. The first dopamine binding aptamer assessed was a DNA aptamer, the binding of which had been previously validated through the aptamer-based biosensor development reported by several independent research groups. The second aptamer investigated was the result of a novel in vitro selection experiment described herein. Our data suggest that systemic administration of the modified liposomes led to delivery of the dopamine aptamers into the brain. Fluorescence microscopy revealed differential distribution of fluorescence based on the presence or absence of the transferrin receptor aptamer on the surface of fluorescently modified liposomes. In a behavioral experiment using cocaine administration to induce elevated concentrations of neural dopamine, systemic pretreatment with the dopamine aptamer-loaded liposomes reduced cocaine-induced hyperlocomotion. Multiple controls including a transferrin-negative liposome control and transferrin-positive liposomes loaded with either a nonbinding, base-substituted dopamine aptamer or a random oligonucleotide were investigated. None of these controls altered cocaine-induced hyperlocomotion. Chronic systemic administration of the modified liposomes produced no deleterious neurobehavioral or neural degenerative effects. Importantly, this work is one example of an application for this versatile multiaptamer payload/targeting system. Its general application is limited only by the availability of aptamers for specific neural targets.

Exploring time-dependent changes in conditioned place preference for food reward and associated changes in the nucleus accumbens.

The conditioned place preference (CPP) procedure has been used to study the incubation of craving phenomenon with rewarding drugs such as cocaine and methamphetamine. The present study examined whether rats trained in a CPP behavioral design would display an incubation of craving response for chocolate-flavored pellets or milk chocolate chips at the behavioral and neural levels. Rats were conditioned using an unbiased CPP design then underwent abstinence from food reward for 24 hs, 7, 14, or 28 days at which point they were tested for CPP. Brains underwent immunohistochemical staining for c-Fos and FosB as well as Golgi staining to assess dendritic spine density in the nucleus accumbens (NAc). A time-dependent increase in CPP and entries into the previously paired compartment was observed in the chocolate-flavored pellet group but not the milk chocolate group. Time-dependent neural changes were not directly associated with behavioral outcomes but c-Fos labelling was higher in the chocolate pellet group than controls at the 7-day abstinence period. The behavioral results show that chocolate pellets are rewarding and are associated with long-term behavioral changes but, as evidenced by limited neural changes, these food rewards do not have the same effects on the NAc as drugs of abuse.