Cathinone Associated Memory Deficit and Neurodegeneration

downloadSynthetic derivatives of cathinones often referred to as “bath salts” are obtained from psychoactive alkaloid Khat (Catha edulis). The prevalence of the consumption of cathinones has been growing alarmingly in the United States in the last decade with new structural  analogs emerging globally each of which differs from the other.

Generally cathinones resemble amphetamine and thus are hypothesized to produce cytotoxicity by acting as substrates and/or inhibitors to the monoamine transporters like dopamine transporter (DAT) and norepinephrine transporter (NET). These compounds are synthetically modified to boost their potency by 10 to 100 fold compared to their natural psychostimulant counterpart and enhanced affinity to the DAT, indicative of high compulsive and rewarding behavior. A growing body of evidence points towards abuse liability, dependence, neurocognitive deficits and cardiovascular toxicities associated with synthetic cathinones. Recently synthetic forms of cathinones like 3,4-MDPV (Methylenedioxypyrovalerone), Methylone (3,4-methylenedioxy-N-methylcathinone) and Mephedrone (4-methylmethcathinone) were investigated for their abuse liability, cognitive deficits and neurodegenerative ability (1-3).

The addictive potential of cathinones were recapitulated by intracranial self-administration paradigm in rodents. Interestingly synthetic cathinones displayed dose dependent increase in drug seeking behavior (1-3). Furthermore neurocognitive deficits were observed in spatial and object recognition memory tasks in different studies (1-3). Finally, histological assays indicated prominence of neurodegeneration confined to the frontal cortex part of the brain as quantified by FlouroJade C (FJC) fluorescent marker and accumulation of malondialdehyde (MDA) as a surrogate marker of oxidative stress (1-3). Taken together, use of synthetic cathinones may pose risks for addiction, inducing cognitive deficits and neurodegeneration targeted to the frontal cortex. Additional studies are needed to investigate the neuroimmune and neurochemical mechanism underlying these effects and potential therapeutics to ameliorate associated neurotoxicity.

  1. Sewalia K, Watterson LR, Hryciw A, Belloc A, Ortiz JB and Olive MF (2018) Neurocognitive dysfunction following repeated binge-like self-administration of the synthetic cathinone 3,4 methylenedioxypyrovalerone (MDPV). Neuropharmacology 134, 36-45.
  2. R. Lopez-Arnau, J. Martinez-Clemente, T. Rodrigo et al (2015) Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone Toxicol. Appl. Pharmacol. 286, 27-35.
  3. Motbey CP, Karanges E, Li KM et al (2012) Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion. PLoS ONE 7,e45473.

Salahuddin Mohammed

Department of Biomolecular Sciences

University of Mississippi

 

Keeping Time – The Stars of the Brain

Of all the different types of cells that make up the brain, neurons are invariably the stars of the central nervous system. But what about astrocytes? They’re literally named for their star-like shape! Though many people consider astrocytes to play a supporting role in brain function, new evidence suggests their part may be front-and-center…

Astrocyte Clock (small)A previous Brain Storm blog post discussed the importance of circadian rhythms to general physiology, and how changes in our ‘biological clock’ may influence our ability to learn and remember as we get older. However, a critical question that remains to be answered is: if each of the neurons in the suprachiasmatic nuclei (SCN – the ‘master clock’) have their own independent rhythms, how are they all coordinated? A recent publication from Marco Brancaccio and colleagues provides one possible answer (1). In this work, the authors set out to determine what role astrocytes play in the collective rhythm of the SCN. They began by creating a model which allowed them visualize each cell’s circadian rhythm. To do this, they used specialized viruses which can selectively target either neurons or astrocytes. Using these viruses, they were able to install a fluorescent marker which lights up when the cells’ clock genes are activated. By constantly recording images of these cells, they were able to see that the rhythms of astrocytes and neurons are slightly out of phase!

One of the most fascinating findings from this report involved mice that are functionally arrhythmic. These mice have a mutation in two vital clock genes – Cry1 and Cry2 – which prevents them from exhibiting normal circadian (~24 hour) patterns of activity. Rather, these mice have bouts of activity and rest with no observable pattern. In this experiment, the authors used those same cell type-specific viruses to restore the Cry1 gene to either astrocytes or neurons in the SCN of these mutant mice. Surprisingly, restoration of Cry1 in astrocytes alone was sufficient to reinstate locomotor rhythms in these previously arrhythmic mice!

The relationship of astrocytes and neurons in the SCN is complex, and many more experiments are required to further reveal the influence of astrocytes on circadian rhythms. Nevertheless, this report supports what we’ve known for ages – using only the stars you can tell the time!

  1. Brancaccio, M., Edwards MD. et al. (2019) Cell-autonomous clock of astrocytes drives circadian behavior in mammals. Science 363, 187-192.

Erik Hodges

Department of Biomolecular Sciences

University of Mississippi

How Coincidence Detectors and G-Proteins Help Us Learn and Remember

Understanding and identifying the molecular mechanisms responsible for Pavlovian or classical conditioning remains a significant goal in neurobiology. Drosophila melanogaster, or fruit flies, have been used as a model organism to investigate learning and memory on a functional and behavioral level. They learn to associate an odor, or the paired of a conditioned stimulus (CS+) to an electric shock (unconditioned stimulus or US). This type of associative learning is important for approach and avoidance behaviors from flies to humans.

Coincidence detection is the process by which a neuron or neural circuit can encode information by detecting the occurrence of temporally close but spatially distributed input signals. The canonical view of how Pavlovian conditioning occurs is through what is called the CS+/US temporal coincidence detection (see Figure). Adenylyl cyclase (AC) has been implicated in memory formation as a coincidence detector and is the best-characterized effector regulated by G-proteins. AC catalyzes the formation of cAMP, a secondary cellular messenger, from ATP. There is an increase in cAMP production that occurs through integration of information from the CS+ and information from the US. cAMP deficient flies like rutabaga mutants have been shown to have a deficit in learning while dunce mutants, defective in cAMP degradation, are also impaired in learning and memory.

Maria NJbC

G-proteins, such as G(o), are involved in associative learning (1) and have also been shown to play a role in neurodegenerative diseases such as Alzheimer’s disease. G(o) proteins are activated by numerous G protein-coupled receptors (GPCRs) and by amyloid precursor protein (2). Through work done in the Roman lab, a new signaling pathway required for the formation of associative memory has been attributed to G(o) proteins where G(o) is required to generate a differential conditioned stimulus salience during discriminative learning (3). Understanding coincidence detectors and the function of G-proteins in the regulation of cellular effectors will help reveal the mechanisms involved in how we learn and remember.

  1. Ferris, J., G. Hong, L. Liu, & G. Roman. (2006). G(o) signaling is required for Drosophila associative learning. Nature Neuroscience, 9, 1036-40.
  2. Sola Vigo, F., Kedikian, G., Heredia, L., Heredia, F., Anel, A. D., Rosa, A. L., & Lorenzo, A. (2009). Amyloid-beta precursor protein mediates neuronal toxicity of amyloid beta through Go protein activation. Neurobiol Aging, 30, 1379-1392.
  3. Zhang, S. & Roman, G. (2013). Presynaptic inhibition of gamma lobe neurons is required for olfactory learning in Drosophila. Current Biology, 23, 2519-2527.

Maria Pena

Department of Biology

University of Mississippi

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).

GauravA 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, Gβγ 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).

Asdownload 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.

Chyna-RaeIn 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.

CBDIn 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

GuestSpeakerFlyer_AnastasioHosted 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).

igf astrocytesAstrocytes 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