Accounts by Former Fellows

 The Grass Fellowship in Neuroscience at the MBL provides a unique environment for junior scientists to conduct research. A few of the past fellows have given us a more detailed account of their scientific expectations and achievements during the Fellowship and how it has helped them in their careers. 

GABA in Squid I

GABA in Squid II

Sensing Electric Fish

Complex and Chaotic Vocal Signals

Striatal Neurons

 

Discovery of GABA receptors in squid.

By Agenor Limón (fellow in 2009)

Since its squiddescription by John Zachary Young in 1938, there is no doubt that the squid stellate ganglion giant synapse has been a remarkable experimental model for understanding the nervous system. From the discovery of the ionic bases of the action potential (Hodgkin and Huxley, 1952) and the description of the calcium dependence of neurotransmitter release (Miledi, 1973; Llinas 1983) to studies of long-term modifications of neuronal activity molded by experience during ontogeny (Preuss and Gilly, 2000), the giant synapse has been fundamental for discoveries that have transcended biological kingdoms to explain some of the basic principles of how our own brain works. However, despite this accumulated knowledge, there remains a surprising scarcity of information about neurotransmitter receptors at synapses of the squid stellate ganglion or brain. In particular, inhibitory neurotransmission in the squid remains largely unexplored. The identity of potential inhibitory receptors in cephalopods is not known, thus precluding the molecular analysis of excitation-inhibition mechanisms.  

Agenor Limon, a 2009 Grass Fellow, used the summer at the Grass Laboratory to search for inhibitory neurotransmitter receptors in the nervous system of the squid, in particular for receptors to GABA, the principal inhibitory neurotransmitter in mammals. One approach consisted of expressing mRNA isolated from squid in a heterologous system; however this method was not successful, probably due to the low mRNA expression of inhibitory receptors in invertebrates. However, an alternative method called microtransplantation of cellular membranes (developed in the lab of Ricardo Miledi, a previous Grass Fellow) enabled identification, for the first time, of GABA receptors in the squid.  The idea was that if GABA receptors were present in cellular membranes of the squid, then it would be possible to isolate those membranes and microtransplant them in Xenopus oocytes. The microtransplanted receptors could then be pharmacologically tested by electrophysiological methods. Because native oocytes do not express GABA receptors, any GABA response elicited in oocytes microtransplanted with squid membranes must arise from squid GABA receptors. After several dissections (and many plates of calamari in salsa verde, calamari sauteed and in sriracha sauce), oocytes microtransplanted with stellate ganglia became responsive to GABA, glutamate and carbachol indicating the successful transplantation of receptors to GABA, glutamate and acetylcholine. Oocytes microtransplanted with synaptosomes from optic lobe membranes responded to carbachol and were also sensitive to changes in voltage. These experiments demonstrated the presence of GABA receptors in cephalopods, and the ability to determine pharmacological parameters of native membrane receptors when no gene is described or from low expressing membrane receptors. In the summer of 2011 another Grass Fellow, Luca Conti, used the microtransplantation method to continue the pharmacological characterization of GABA receptors in squid.  The joint work of Limon and Conti lead to the first published description of GABA receptors in cephalopods (Conti et al., 2013).Age

Interestingly, the success of the microtransplantation method in finding low abundance neurotransmitter receptors in squid has relevance for studying changes in neurotransmitter receptors in the Alzheimer diseased (AD) brain. A paradox in AD is that excitatory neurotransmission is severely disrupted, yet the brain is prone to hyperexcitable states (Liepert et al., 2001). Back at the University of California at Irvine, Limon pursued further research using the same methodology used in the squid to demonstrate a strong dysfunction of GABAergic neurotransmission in the AD brain and a remodeling of GABA receptors that may underlie some of the changes that lead to hyperexcitability in AD (Limon et al., 2012). The microtransplantation and reactivation of human neurotransmitter receptors from frozen brains also demonstrated changes in the senescent brain that may help to understand synaptic dysfunction in normal aging.   

During his tenure as a Grass Fellow, Limon also collaborated with Jorge Contreras in his studies of the gating mechanism of human connexin 26. That work led to an abstract presentation (Contreras et al., 2010). Of his experience as a Grass Fellow, Limon says, “The summer at the Grass Laboratory was, with no doubt, one of the most important experiences in my life. Sharing time and space with the people in the Grass Laboratory taught me more about the power of interdisciplinary and collaborative work, than any book, journal or a seminar could. The experience to mount a rig from scratch, administrate the funds, long days and nights of experiments and the interaction with other Grass Fellows, professors, researchers, course students and all the worldwide community gathering at the MBL leave a watermark in all the work that comes afterwards.”

Agenor Limón is currently a Project Scientist with Prof. Ricardo Miledi at the University of California, Irvine (UCI))

References

In Bold publications from the 2009 Grass fellowship:

Conti L, Limon A, Palma E, Miledi R (2013) Microtransplantation of cellular membranes from squid stellate ganglion reveals ionotropic GABA receptors. Biol Bull 224: 47-52.

Contreras JE, Limon A, Lopez-Rodriguez A (2010) Gating by Voltage and Ca2+ in Human Connexin (cx26) Hemichannels. Biophys. 98: 92a.

Hodgkin A, Huxley A (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117: 500–544.

Liepert J, Bär KJ, Meske U, Weiller C (2001) Motor cortex disinhibition in Alzheimer's disease. Clin Neurophysiol. 112: 1436–41.

Limon A, Reyes-Ruiz JM, Miledi R (2012) Loss of functional GABAA receptors in the Alzheimer diseased brain. Proc. Nat. Acad. Sci. 109: 10071-6.

Llinas R. Sugimori M, Bower JM (1983) Visualization of depolarization-evoked presynaptic calcium entry and voltage dependence of transmitter release in squid giant synapse. Biol Bull 165: 529-530.

Miledi R (1973) Transmitter release induced by injection of calcium ions into nerve terminals. Proc R Soc Lond B Biol Sci. 183: 421-425.

Preuss T, Gilly WF (2000) Role of prey-capture experience in the development of the escape response in the squid Loligo opalescens: a physiological correlate in an identified neuron. J Exp Biol. 203(Pt 3):559-65.

Young JZ (1938) The functioning of the giant nerve fibres of the squid. J. Exp. Biol. 15: 170 -85

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Characterization of GABA receptors in squid.

Luca Conti (Fellow in 2011)

ContiWhile the physiology of squid giant axons has been extensively studied, almost nothing is known about the distribution and function of the neurotransmitters that mediate synaptic transmission. Although spontaneous and evoked inhibitory synaptic potentials due to chloride fluxes have been recorded in the stellate ganglion of squids (Miledi, 1972) and in slices of the cuttlefish optic lobe (Chrachri and Williamson, 2003), so far neither the neurotransmitter mediating those potentials nor their membrane receptors have been characterized. Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in mammals, has been found at low levels in the octopus brain (Osborne, 1971). Moreover, mRNA for GABAR-like receptors in invertebrates is also limited (Harvey et al., 1991). In the summer of 2009 Agenor Limon, a senior postdoc from Ricardo Miledi’s lab, moved from Irvine to Woods Hole to study, as a Grass fellow, GABA as a neurotransmitter at squid synapses. In the Grass lab, Limon demonstrated that GABA is a neurotransmitter in the squid stellate ganglion, a cluster of neurons responsible for the contraction of the mantle and the motion of the animal. In 2011, during my PhD in Neurophysiology at the University “Sapienza” of Rome, I decided to apply for a Grass fellowship with the aim of characterizing these GABA-evoked currents at the squid giant synapse and continue Limon’s work. This was possible because of a strong collaboration between my PhD supervisor, Eleonora Palma (Grass fellow in 1997), and Ricardo Miledi (Grass fellow in 1955). That summer was one of the most exciting and productive of my life!

Since direct application of GABA by iontophoresis in the stellate ganglion is difficult, mainly because of the morphology of the synapses and the large amount of connective tissue covering the ganglion, and because of the low aboundance of mRNA for GABA-like receptors in invertebrates, we performed voltage clamp experiments using membrane homogenates extracted from the stellate ganglion of the squid and microtransplanted into Xenopus oocytes. With this approach, vesicles containing receptors from the stellate ganglion were incorporated into the surface of the oocyte, bypassing the machinery of the host cell and yielding already assembled receptors. This method has been used successfully in different species, from Torpedo fish to human, but it had not been tried on the nervous system of an invertebrate. conti data2The application of GABA to Xenopus oocytes injected with membranes from squid stellate ganglia elicited currents of –48.3 ± 18.0 nA, indicating that squid express ionotropic GABARs that were successfully transplanted to the oocytes (Fig. 2).

Next, we characterized GABARs from squid stellate ganglia. The reversal potential for the GABA-evoked currents was –18.3 ± 0.9 mV (n = 6), near the predicted value of -26 mV, suggesting that chloride is the main carrier. GABARs were activated by GABA with a half maximal effective concentration (EC50) of 98 M (Fig. 3A) and were inhibited by zinc with a half maximal inhibitory concentration (IC50) of 356 ± 6 M (Fig. 3B). We also examined the effects of 100 M bicuculline, a competitive antagonist of GABAA receptors, in oocytes injected with membranes from squid stellate ganglia. Interestingly, bicuculline reduced the maximum amplitude of IGABA by 23%. This partial blockage of squid GABA receptors by bicuculline is very similar to what has been reported for GABA receptors in other invertebrates (Lunt, 1991) and for GABARs composed by  subunits in vertebrates (Polenzani et al., 1991).

Collectively, these data support the role of GABA as an ionotropic neurotransmitter in cephalopods, acting through chloride-permeable membrane receptors. This was the first direct evidence that GABA is a neurotransmitter at the squid stellate ganglion. This work was published in February 2013 in The Biological Bulletin (Conti et al., 2013): all four authors were Grass fellows, from 1955 to 2011.conti data3

The Marine Biological Laboratory represented the ideal place to carry out this research, because of the excellent fish facility and the scientific environment. All the experiments were discussed almost daily with the other fellows, that I consider now good friends, with the associate-director and director of the Grass lab, and also with “well known” scientists present at MBL. All the suggestions, and the exchange of ideas, that arose during these conversations were fundamental for the development of the project and, most important, for my scientific growth.

 

 

References

Chrachri, A., and R. Williamson. 2003. Modulation of spontaneous and evoked EPSCs and IPSCs in optic lobe neurons of cuttlefish Sepia officinalis by the neuropeptide FMRF-amide. Eur. J. Neurosci. 17: 526–536.

Conti L, Limon A, Palma E, Miledi R. 2013. Microtransplantation of cellular membranes from squid stellate ganglion reveals ionotropic GABA receptors. Biol Bull. 224(1): 47-52.

Harvey, R. J., E. Vreugdenhil, S. H. Zaman, N. S. Bhandal, P. N.Usherwood, E. A. Barnard, and M. G. Darlison. 1991. Sequence of a functional invertebrate GABAA receptor subunit which can form a chimeric receptor with a vertebrate alpha subunit. EMBO J. 10: 3239–3245.

Lunt, G. G. 1991. GABA and GABA receptors in invertebrates. Semin. Neurosci. 3: 251–258.

Miledi, R. 1972. Synaptic potentials in nerve cells of the stellate ganglion of the squid. J. Physiol. 225: 501–514.

Osborne, N. N. 1971. Occurrence of GABA and taurine in the nervous systems of the dogfish and some invertebrates. Comp. Gen. Pharmacol.2: 433–438.

Polenzani, L., R. M. Woodward, and R. Miledi. 1991. Expression of mammalian gamma-aminobutyric acid receptors with distinct pharmacology in Xenopus oocytes. Proc. Natl. Acad. Sci USA 88: 4318–4322.

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Measuring natural inputs to the electrosensory system of freely swimming electric fish using a miniature wireless telemetry system.

by Haleh Fotowat (Fellow in 2010)

To understand the neural mechanisms underlying sensory processing, one has to see them in the context of the animal’s natural behavior. Although many researchers have investigated the processing properties of sensory systems with a view to naturalistic stimulus conditions, there is still surprisingly little information available on the spatiotemporal statistics of natural scenes as experienced by animals engaged in behaviors that involve the concomitant movement of their sensory receptor arrays.

For my Grass project, I proposed measuring the natural electrosensory input in freely swimming weakly electric fish, Apteronotus albifrons using a miniature wireless telemetry system (Fig. 2A). fotowatfig2I had used the same system during my PhD studies in the lab of Dr. Fabrizio Gabbiani to record neural and muscle activity in freely moving locusts during their looming-evoked escape behavior (Fotowat et al., 2011). This project was inspired by my general interest in studying neural mechanisms underlying natural sensory-evoked behavior, the wealth of existing knowledge about the anatomy and physiology of the electro-sensory system of weakly electric fish (Bullock, 1995), and the scarcity of knowledge about natural electro-sensory input. These fish use a self-generated quasi-sinusoidal electric field for electrolocation and electro-communication. Thousands of cutaneous electroreceptors detect changes in the transdermal potential (TDP) as the fish interact with conspecifics and the environment. As the electroreceptors are distributed on the fish’s skin, their physical input can be measured transdermally and their position can be determined by tracking the fish’s body. During the summer in the Grass lab, I experimented with various methods for making the wireless system waterproof and mounting it on the fish (Fig. 2B).

I also developed software for tracking the shape of the fish’s body as well as its position relative to the tank. By the end of the summer I had preliminary recordings of the TDP in freely swimming fish. The data from these recordings were later published in a technical paper (Harrison et al., 2011). I was excited about this novel method, so I continued working on it after starting my post-doctoral research in the lab of Dr. Rüdiger Krahe. There, I used a related species, Apteronotus leptorhynchus, to characterize the natural statistics of the TDP caused by swimming movements and interaction with a conspecific. I found that swimming movements resulted in low-frequency TDP amplitude modulations (AMs, Fig. 3A). fotowatfig3Interacting with a conspecific caused additional AMs because of the interaction of their electric fields, with the amplitude of the AMs (envelope) varying at low frequencies due to mutual movements (Fig. 3B). Combining a computational model of the electric field (Chen et al., 2005) with video tracking of movements, I could predict the wirelessly measured variations in TDP (Fig. 4). Moreover, I showed that distinct swimming patterns cause characteristic spatio-temporal sensory input correlations, which contain information that may be utilized by the brain to guide behavior.

Interestingly, both AMs and envelopes showed a power-law relationship with frequency, indicating long-range temporal correlations and scale invariance. Power-law scaling in space and time is a ubiquitous phenomenon in nature (Gisiger 2001). For example, spectral power of images of natural scenes and the envelopes of natural sounds follow a power-law relationship with frequency (Ruderman and Bialek 1994, Attias and Schreiner 1997). Here we show that power-law scaling of sensory input is maintained even when natural movements of the sensor array are taken into account, a factor that had not previously been included in measurements of sensory input statistics.

The information contained in the amplitude and envelope of sensory inputs is important for sensory processing across sensory modalities and animal species. Processing of the stimulus and its envelope is commonly accomplished through parallel linear and nonlinear pathways and likely shares common mechanisms across sensory systems. These mechanisms can be further investigated in future, taking into account the power-law statistics of sensory stimuli that are evoked as a result of the natural movements of the organism. Results from these experiments are currently in-press in the Journal of Neuroscience (Fotowat et al., 2013).

The Grass Fellowship enabled me to experiment with and develop a system for underwater wireless electrophysiological recordings in small freely swimming fish, a novel technique that had not been tested before. It also provided me with a great scientific environment to discuss the challenges and difficulties involved with the project and to get helpful feedback and comments from other Grass fellows, Grass Directors, and MBL investigators, especially Drs. Steve Zottoli and Allen Mensinger. Moreover, spending the summer at the MBL has given me much scientific inspiration, helped me grow significantly as an independent researcher, and helped me make valuable connections with other scientists.

References

Attias H, Schreiner CE (1997) Temporal low-order statistics of natural sounds. Advances in Neural Information Processing Systems 9:27–33.

Bullock TH, Hopkins CD, Fay RR, editors (2005) Electroreception Springer, New York.

Chen L, House J, Krahe R, Nelson M (2005) Modeling signal and background components of electrosensory scenes. J Comp Physiol A 191:331–345.

Fotowat H., Harrison R. R. Gabbiani F. (2011), “Multiplexing of motor information in the discharge of a collision detecting neuron during escape behaviors”, Neuron 69(1):147-58.

Fotowat H, Harrison RR, Krahe R (2013) The Statistics of the Electrosensory Input in Freely Swimming Weakly Electric Fish, Apteronotus leptorhynchus. In press, J Neurosci.

Gisiger T (2001) Scale invariance in biology: coincidence or footprint of a universal mechanism? Biol Rev Camb Philos Soc 76:161–209.

Harrison RR, Fotowat H, Chan R, Kier RJ, Olberg R, Leonardo A, Gabbiani F (2011) Wireless neural/EMG telemetry systems for small freely moving animals. IEEE Trans Biomed Circuits Syst 5:103–111.

Ruderman DL, Bialek W (1994) Statistics of natural images: scaling in the woods. Phys Rev Lett 73:814–817.

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Central Neural Coding of Complex and Chaotic Vocal Signals.

by Coen Elemans (Fellow in 2009)

ElemansSound communication is fundamental to many social interactions and essential to courtship and agonistic behaviors in many vertebrates. The swimbladder and associated muscles in batrachoidid fishes is a unique vertebrate sound production system, wherein fundamental frequencies are determined directly by the firing rate of a vocal-acoustic neural network that drives the contraction frequency of superfast swimbladder muscles. However, the oyster toadfish boatwhistle call starts with irregular sound waves indicative of deterministic chaos. Complex acoustic signals containing chaos have been observed across vertebrates, including fish, frogs, birds and mammals. This complexity can be harnessed to convey vast amounts of information. In order to be informative, however, the signals must also be reliable. The main goal of my Grass fellowship project was to test if the complex waveform in the toadfish boatwhistle is an emergent property of the peripheral sound-producing system or originates in the vocal motor network.

We recorded sound and swimbladder muscle activity in awake, freely-behaving toadfish during motor nerve stimulation, and recorded sound, motor nerve and muscle activity during spontaneous grunts. The results suggest that complex sound signals are not caused by rhythmic motor volleys, but are a result of arrhythmic recruitment of swimbladder muscle. This supports the hypothesis that the irregular start of the boatwhistle is encoded in the vocal pre-motor neural network, and not caused by peripheral interactions with the sound-producing system. toadfishSound production system demands across vocal tetrapods have selected for muscles and motor neurons adapted for speed, executing equivalently complex neural instructions for complex vocalizations. In addition, I measured sound production efficiency in toadfish as a function of temperature. In the last days of my Fellowship, I started to develop a new experimental approach to measure length changes during contraction of superfast muscle using high-speed imaging. We successfully used this technique after my Grass Fellowship to measure superfast laryngeal muscles in bats (Elemans et al., 2011) and toadfish (in prep).

For me the Grass program was nothing short of a life-altering experience. I had never worked so closely together with a group of young eager scientists all in a similar phase of their career. I also have never experienced another environment with such an incredible concentration of top scientists, and with such a heart-warming and welcoming atmosphere as at the MBL. It feels like being part of a big family now. Where normally good advice can be hard to get, at the MBL we could dream up an experiment one evening, consult the imagining expert on the 3rd floor and the calcium expert on the 4th floor the next morning, and do the experiment in the afternoon. Completely amazing… The Grass program is one of the very rare places where conducting high-risk projects is still possible. A place where you can be guided by inspiration, passion and discovery.

Coen Elemans is currently Assistant Professor at the Institute of Biology at the University of Southern Denmark (www.celemans.com).

References

Elemans CPH, Mead AF, Jakobsen L, Ratcliffe JM. 2011. Superfast muscles set maximum call rate in echolocating bats. Science. 333: 1885-8.

 

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Sex differences in striatal neurons

by John Meitzen (Fellow in 2011)

MeitzenThe scientific goals for my summer as a Grass Fellow were straightforward: (1) learn whole cell patch clamp technique in rodent brain slices of striatum; (2) test whether striatal neuron electrophysiological properties varied with sex; (3) investigate how adrenergic receptor activation modulated striatal neuron electrophysiology and whether this varied by sex. These questions are important both for basic neurobiology (i.e., how are neural systems tweaked by sex-specific neuromodulators and genetics) and biomedicine (the phenotypes of multiple striatal pathologies differ by sex). Among other things, the striatum plays an influential role regulating how the brain responds to many drugs of abuse, and the phenotypic response to drugs of abuse differs by sex (Becker and Hu, 2008). Other striatal-related pathologies show sex differences in phenotype as well. One of the more famous is L-DOPA-induced dyskinesia. L-DOPA is the most commonly employed treatment for the motor symptoms of Parkinson’s Disease and one of the drug’s primary targets is the striatum. While L-DOPA treatment is often successful in restoring motor function in Parkinson’s Disease patients, its continual use can lead to severe side effects, including the motor disorder dyskinesia. L-DOPA-induced dyskinesia has a higher incidence and severity in females than in males (Haaxma et al., 2007; Lyons et al., 1988; Pavon et al., 2010).

These well-known sex differences in striatal-related pathologies, along with a growing literature describing sex differences in striatal neuron function and gene expression (i.e., Mermelstein et al., 1996; Wissman et al., 2011; Chen et al., 2009) inspired me to focus my Grass project on sex differences in the electrophysiological properties of striatal neurons. I had done a lot of electrophysiology as an undergraduate and graduate student, but it had been three years since I had last patched a neuron, and certainly not in rodents. I knew that when I became a PI that I wanted to re-incorporate electrophysiology into my research program. The challenge was that my post-doctoral laboratory was not set up well for the technique I wanted to pursue, whole cell patch clamp in acute brain slices. With the support of my post-doctoral advisor, Paul Mermelstein, I applied for and was awarded a Grass Fellowship to work on this question. The Grass lab Associate Director was able to get all of the equipment I needed to build a rig (Fig. 1). It took weeks of hard work to teach myself the new skills and re-learn old ones (and some help along the way from the Grass lab Director, other Grass Fellows, MBL staff and Zeiss, Dage and Sutter representatives), but by the end I could make healthy brain slices, visualize neurons using IR-DIC, and patch and record (Fig. 2A-C).Meitzen data

Once I began recording neurons regularly, I was able to focus on analyzing the data and to start testing the hypotheses from my other two goals. Based upon the literature, I suspected that there would be subtle sex differences in striatal neuron physiology, especially in response to neuromodulators such as steroid hormones and catecholamines (i.e., Meitzen et al., 2013; Mermelstein et al., 1996; Grove-Strawser et al. 2010; Becker and Hu, 2008). The body of work generated while testing this speculation became part of the pilot data that I used during my job search for a PI position, and I’m still building upon it now as a new professor in the Department of Biological Sciences and the Keck Center for Behavioral Biology at North Carolina State University. Setting up the rig and experiments in the Grass Lab was great preparation for setting up my lab here at NCSU.

Finally, I’d like to end by busting five myths about the Grass Fellowship. First, you don’t have to work with fish. (although you certainly can!). I worked with rats. Second, you don’t have to do electrophysiology (I did, but others in the lab did not). Third, you don’t have to be previously associated with the MBL or have a PI involved with the Grass program (I didn’t). Fourth, you don’t have to be single (My wife and baby came too, and my daughter took her first steps at the MBL). And finally, the biggest myth of all is that you can’t get enough done over three months to justify the time away from your home laboratory. The reality is that a lot can happen, especially given the environment and resources offered by the Grass Lab and MBL. It’s important to have clearly defined goals, maintain focus, work hard, and have fun.

 

John Meitzen is currently Assistant Professor at North Carolina State University

References

Becker J. B., and Hu M. 2008 Sex differences in drug abuse. Front Neuroendocrinol. 29: 36-47

Chen X., Grisham W., and Arnold A. P. 2009 X chromosome number causes sex differences in gene expression in adult mouse striatum. Eur J Neurosci. 29: 768-776.

Grove-Strawser D., Boulware M. I., and Mermelstein P. G. 2010 Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons. Neuroscience 170: 1045-1055

Haaxma C. A., Bloem B. R., Borm G. F., Oyen W. J., Leenders K. L., Eshuis S., Booij J., Dluzen D. E., and Horstink M. W. 2007 Gender differences in Parkinson's disease. J Neurol Neurosurg Psychiatry. 78: 819-824.

Lyons K. E., Hubble J. P., Troster A. I., Pahwa R., and Koller W. C. 1998 Gender differences in Parkinson's disease. Clin Neuropharmacol. 21: 118-121.

Meitzen J., Perry A. N., Westenbroek C., Hedges V. L., Becker J. B., and Mermelstein P. G. 2013 Enhanced striatal β1-adrenergic receptor expression following hormone loss in adulthood is programmed by both early sexual differentiation and puberty: a study of humans and rats. Endocrinology 154: 1820-1831

Mermelstein P. G., Becker J. B., and Surmeier D. J. 1996 Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor. J Neurosci. 16: 595-604.

Pavon J. M., Whitson H. E., and Okun M. S. 2010 Parkinson's disease in women: a call for improved clinical studies and for comparative effectiveness research. Maturitas. 65: 352-358

Wissman A. M., McCollum A. F., Huang G. Z., Nikrodhanond A. A., and Woolley C. S. 2011 Sex differences and effects of cocaine on excitatory synapses in the nucleus accumbens. Neuropharmacology 61: 217-227

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