Brain Awareness Week 2019 and Neuroscience Showcase

Your Brain on Drugs: How Addiction Changes Your Brain

Neuroscience Showcase 2019

Brain Awareness Week news release

 

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Mechanisms of learning and memory: Lessons from flies

Associative learning is a form of learning that helps us to predict an event (i.e. reward or punishment) from a stimulus (i.e. neutral stimulus) that has been previously associated with that event. Decoding the underlying molecular mechanism involved in this association has been a goal in Neurobiology of Learning and Memory. In the past couple of decades, there has been a significant progress in understanding associative learning and memory in the fly Drosophila using olfactory learning. In this learning paradigm, flies are presented with an odor (conditioned stimuli, CS+) paired with an electric shock (unconditioned stimuli) and another odor (CS-) without electric shock (1).

A heterotrimeric G_(o) signaling protein coupled with G protein receptors, known to be expressed through the vertebrate brain, plays an important role in learning and memory. Also, mushroom bodies, a pair of structures present in the brain of insects, are known to play a role in olfactory learning and memory. The mushroom bodies are divided into 3 distinct classes of neurons: α/β, α’/β’, and γ lobe neurons. Inactivation of the G_(o) protein through the expression of a pertussis toxin (PTX) in these mushroom bodies leads to disruption in memory formation (1,2). Expressing PTX is in α/β and γ lobe neurons causes a severe loss of short term memory however expressing PTX either in α/β or γ lobe alone causes partial loss of short term memory (2,3). A study suggests that presynaptic inhibition through G_(o) activation  is necessary in γ lobe neurons for olfactory learning.  In vertebrate systems, G_βγ subunit of heterotrimeric G protein has been shown to inhibit presynaptic transmission through inhibition of voltage gated calcium entry, activation of inward rectifying K+ channels or by direct interaction with vesicle fusion machinery SNARE complex (see Figure) (3).

The role of heterotrimeric G_(o) signaling is necessary for olfactory associative memory formation within α/β and γ lobe. Further elucidation of this pathway within these neurons would provide the underlying principles of the molecular mechanisms of memory formation.

1. Ferris, J., Ge, H., Liu, L. and Roman, G. (2006). G(o) signaling is required for Drosophila associative learning. Nature Neuroscience, 9, 1036-1040.
2. Madalan, A., Yang, X., Ferris, J., Zhang, S. and Roman, G. (2011). G(o) activation is required for both appetitive and aversive memory acquisition in Drosophila. Learning & Memory, 19, 26-34.
3. Zhang, S. and Roman, G. (2013). Presynaptic Inhibition of Gamma Lobe Neurons Is Required for Olfactory Learning in Drosophila. Current Biology, 23, 2519-2527.

Gaurav Shrestha

Department of Biology

University of Mississippi

The Aging Cerebral Clock

How do you keep track of time? The watch on your wrist? The phone in your pocket? A calendar? A Sundial? Though the sun may seem like an antiquated timepiece in the modern world, that’s exactly what your body uses! Many, if not all, of our physiological processes exhibit circadian rhythms – daily patterns that correspond to the cyclic relationship of the Sun and Earth (1). Deep within our brain, there are specialized groups of neurons called the suprachiasmatic nuclei (SCN) that function like a biological clock. These neurons are found directly above the optic tract (the bundle of nerves that carries information from your eyes to your brain) and make sure that all of our daily biological activities occur on time. Collectively, these neurons regulate the sleep/wake cycle, physical activity and alertness, food-seeking behavior, and many of our other vital physiological processes (see Figure).

As we age, our circadian rhythms become less consistent and less pronounced. This is perhaps most evident in our daily sleep/wake cycle. Additionally, aged individuals also report problems in learning and memory. One theory for how our brain learns and stores memory, states that neurons must grow and make new connections with other neurons. This process, known as synaptogenesis, requires the production of new cellular building blocks – proteins. The blueprints for these new proteins come in the form of DNA and RNA. Previous work suggests that the aging brain has difficulty converting DNA to RNA, and that this process might explain why synaptogenesis declines with age (2).

A recent publication from Kwapis and colleagues suggests one possible mechanism relating these two observations (3). Their work indicates that the circadian gene Period1 (Per1) is vital to memory formation in the aging brain. Furthermore, restoration of Per1 transcription in the aging brain via deletion of a repressive DNA-binding protein (HDAC3) can improve performance of aged mice. Taken together their findings provide additional evidence that the molecular mechanisms responsible for circadian rhythms are vital to proper brain function.

Although it isn’t practical for us to delete the HDAC3 gene from our brains as we get older, maintaining a consistent daily rhythm is a bit easier. So do yourself a favor – soak up some sunshine, and try not to stay up all night watching Netflix.

1. Pittendrigh, Colin S. (1993) Temporal organization: reflections of a Darwinian clock-watcher. Annual review of physiology 55, 17-54.
2. Penner, M. R., Roth, T. L., Barnes, C. A. & Sweatt, J. D. (2010) An epigenetic hypothesis of aging-related cognitive dysfunction. Front Aging Neurosci. 2, 9.
3.  Kwapis, Janine L., et al. (2018) Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nature communications 9, 1-13.

Erik Hodges

Department of Biomolecular Sciences

University of Mississippi

Healing hormones: Lack of estrogen reveals spatial memory deficits after damage to the cerebellum

Probably the last thing on women’s minds during the end of their reproductive life is, oddly enough, their minds. Reducing symptoms like hot flashes and low libido are usually the top priorities for menopausal women who are considering hormone replacement therapy but the real benefit of supplemental estrogen may be its ability to protect the brain. Postmenopausal women who take estrogen supplements show less decline in cognitive abilities than women with no hormone replacement (1). This discovery led to the idea that estrogen can prevent deterioration of the brain and perhaps even protect it from damage. Estrogen is involved in many processes in the brain and, importantly, is made within the brain itself. Quite intriguingly, the synthesis of estrogen is increased following a brain injury (2). This suggests that estrogen is involved in a natural healing process initiated by the brain as a response to injury.

In my lab, we study the relationship of estrogen and recovery from brain damage. We use a songbird, the zebra finch, as a model organism since the songbird brain recovers quickly from injury (3). Songbirds also have a long history of informing research into the actions of hormones in the brain (3). We have found that birds with a lack of estrogen do not recover as well after cerebellar injuries as birds with normal levels of estrogen. These birds with blocked estrogen synthesis (Les+Let) are unable to learn how to complete a spatial maze as quickly as both uninjured birds (Sham) and birds with cerebellar injuries that have estrogen available, whether the estrogen is natural (CbLes) or given by injection to replace estrogen lost in birds with blocked estrogen synthesis (E+Let; see Figure). This suggests that natural levels of estrogen in the brain are sufficient to enable recovery from small brain injuries and restore lost cognitive functions like spatial memory. Through use of this model organism, we will investigate potential mechanisms for the protective actions of estrogen. Most likely, estrogen acts to prevent the secondary wave of damage that follows a brain injury but estrogen may be involved in the birth of new neurons to replace those that were damaged. We believe this work will be important not only in enhancing our understanding of the brain’s natural healing abilities but also in informing future work that may lead to treatment of brain damage through the promotion of endogenous protective mechanisms.

1. Foy, M.R., Henderson, V.W., Berger, T.W. & Thompson, R.F. (2000) Estrogen and Neural Plasticity. Current Directions in Psychological Science, 9, 148-152.
2. Peterson, R.S., Fernando, G., Day, L.B., Allen, T.A., Chapleau, J.D., Menjivar, J., Schlinger, B.A. & Lee, D.W. (2007) Aromatase expression and cell proliferation following injury of the adult zebra finch hippocampus. Developmental Neurobiology, 67, 1867-1878.
3. Schlinger, B.A. (2015) Steroids in the Avian Brain: Heterogeneity across Space and Time. Journal of Ornithology, 156, 419–424.

Chyna-Rae Dearman

Department of Biology

University of Mississippi

Cannabidiol: A controlled substance against the evidence

Cannabis sativa contains around 400 natural compounds. The main two ingredients are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC mediates a psychoactive effect with a rewarding action of cannabis through binding to cannabidiol receptor type 1 (CB1R), which is located mainly in the central nervous system (1). On the other hand, CBD is a non-psychoactive compound that works on CB2R, which is found in the peripheral nervous system (1). CBD seems to lack a drug abuse activity due to the binding to CB1R with a low affinity compared to THC (1).

In the last two decades, several studies suggested that CBD has beneficial uses to treat diseases mainly related to the central nervous system such as multiple sclerosis, Parkinson’s disease, and epilepsy (1, 2). Moreover, other studies showed that CBD improves cognition, neurogenesis (1, 3), with anti-psychotic-like effects (1). All this evidence supports potential CBD usefulness to treat neurological/psychiatric disorders. However, widespread investigation of CBD has been limited due to caution of abuse liability and strict drug scheduling.

In a recent study by Vindez-Martinez and collaborators (1), CBD is investigated as potential drug abuse in mice. Three different behavioral tests were used for evaluating drug addiction. The reinforcing effects of the CBD (15,30 and 60 mg/kg, ip) were tested by the conditioned place preference (CPP). The withdrawal syndrome symptoms (locomotor and somatic signs) were examined as well (see Figure). Finally, CBD was tested for oral self-administration (50 mg/kg, ip). The result showed that, CBD lacks a drug abuse profile in mice. CBD failed to induce CPP in three different doses. Also, cessation of CBD after 6 days of treatment did not produce withdrawal symptoms. Finally, CBD failed to influence oral self-administration. This information along with the results from other preclinical and clinical studies has encouraged the acceleration of clinical studies needed to elucidate the potential therapeutic use of CBD for the treatment of a wide variety of neuropsychiatric disorders.

1. Viudez-Martínez, A. et al. (2018). Cannabidiol does not display drug abuse potential in mice behavior. Acta Pharmacologica Sinica  0, 1–7.
2. Giacoppo, S. R. et al. (2015). Purified Cannabidiol, the main non-psychotropic component of Cannabis sativa, alone, counteracts neuronal apoptosis in experimental multiple sclerosis. Eur Rev Med Pharmacol Sci. 19, 4906–19.
3. Osborne, A.L. et al. (2017). A systematic review of the effect of cannabidiol on cognitive function: relevance to schizophrenia. Neurosci Biobehav Rev 72, 310-24.

Alaa Qrareya

Department of Biomolecular Sciences

University of Mississippi

SEMINAR_Serotonin:Glutamate Synergy in Substance Use Disorder Relapse-Related Behaviors

Hosted by the BioMolecular Sciences Department, School of Pharmacy

11:00 a.m. – 12:00 p.m., Thad Cochran Research Center, Rm 2066

Dr. Noelle C. Anastasio
Assistant Professor
Dept. of Pharmacology and Toxicology, The University of Texas Medical Branch

IGF-1, Astrocytes and Glutamate in the Aging Brain

Insulin-like growth factor-1 (IGF-1) is a signaling protein that plays an important role in regulating learning and memory. We see a decrease in the levels of IGF-1 in blood circulation, cerebrospinal fluid and brain (hippocampal) tissue in aged rodents (1). Decrease levels of IGF-1 are associated with cognitive decline during aging. Moreover, the decline in cognition is reversible with IGF-1 supplementation (2).

Astrocytes are responsible for maintaining the microenvironment that supports and nurtures neurons. In an aging brain, astrocytes exhibit a stressed state called astrogliosis. These reactive astrocytes secrete substances that further accelerate the process of aging. Additionally, it is known that a loss of IGF-1 leads to astrogliosis. Thus, a loss of IGF-1 can prove to be detrimental for normal functioning of astrocytes. Excitatory neurons in the brain use glutamate to communicate with other neurons. However, too much of glutamate in the synapse leads to excitotoxicity. Astrocytes play a key role to keep the extracellular concentrations of glutamate very low (about 10,000 times lower than the intracellular concentrations). In particular, astrocytes are responsible for the uptake of glutamate from the synapse via Excitatory Amino Acid Transporters 1 and 2 (EAAT1 and EAAT2). The glutamate taken up is then converted to glutamine and then transported back to neurons Glutamine is crucial for neurons in order to synthesize glutamate and also for energy metabolism. The role of astrocytes is critical for neurons for two major reasons: 1) The regulation of glutamate concentrations helps prevent excitotoxicity. 2) Neurons on their own cannot produce glutamine and therefore rely on astrocytes for it. Thus, this vital function of taking excess glutamate performed by the astrocytes, helps protect astrocytic as well as neuronal components of the glutamate-glutamine cycle.

IGF-1 is known to regulate the increase of the expression of EAAT1 transporters in astrocytes (3). Therefore, it is important to investigate how the glutamate uptake as well as the glutamate-glutamine cycle are influenced by IGF-1 signaling and also how these cellular mechanisms contribute to cognitive decline during aging.

1. Ashpole, N. M., Sanders, J. E., Hodges, E. L., Yan, H., & Sonntag, W. E. (2015). Growth hormone, insulin-like growth factor-1 and the aging brain. Experimental Gerontology 68:76-81.2.
2. Sonntag, W. E., Ramsey, M. & Carter, C. S. (2005) Growth hormone and insulin-like growth factor-1 (IGF-1) and their influence on cognitive aging. Ageing research reviews 4: 195-212.
3. Suzuki, K. Ikegaya, Y., Matsuura, S., Kanai, Y., Endou, H. & Matsuki, N. (2001) Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes. J Cell Sci 114: 3717-3725.

Disha Prabhu

Department of Biomolecular Sciences

University of Mississippi