254 Matching Annotations
  1. Last 7 days
    1. J. A. Kessler, J. E. Adler, M. C. Bohn, I. B. Black, Science 214, 335 (1981); J. A. Kessler, J. E. Adler, W. O. Bell, I. B. Black, Neuroscience 9, 309 (1983)

      In these studies, the authors examined the role of the neurotransmitter substance P in nerve ganglia. The authors confirmed that the activity of substance P is dependent on sodium currents, changes within the cell, and impulsive activity.

    2. The medullary explants exhibited a 50-fold rise in [Leu]enkephalin within 4 days, after a 2-day lag period, and continued increasing through 7 days, the longest time examined. In contrast, TH activity remained constant throughout, while PNMT decreased 60 percent in the first 4 hours, maintaining a stable plateau thereafter.

      Medullary explants were obtained from adult rats to understand the mechanism behind the different transmitter expression. The TH activity stayed consistent throughout the seven day period. The PNMT enzyme exhibited a 60% decrease in four hours and was maintained at that level for the remainder time period. The [leu]enkephalin showed a 50-fold increase in four days and continued to increase until seven days.

    3. Axotomy of the petrosal neurons, separating the cell bodies from peripheral targets, resulted in a precipitous decline in TH catalytic activity and disappearance of TH immunoreactivity

      Cutting down the axons in the petrosal neurons causes a decrease in TH activity and immunoreactivity. However, there is a certain level of TH recovery after four weeks, which could be due to the regeneration or recovery of the severed axon.

    4. nicotinic receptor stimulation, with consequent depolarization or attendant transmembrane Na+ influx, or both, decrease substance P in mature sympathetic neurons, as in neonatal neurons

      With nicotinic receptor stimulation, the depolarization or the influx of sodium ions across the membrane causes a decrease in substance P in both mature and developing neurons.

    5. tetrodotoxin, which prevents Na+ influx elicited by veratridine, prevented the effects of depolarization

      The sodium influx caused by veratridine was cancelled out by tetrodoxin exposure. Tetrodotoxin blocks the influx of sodium ions thereby stopping depolarization. Hence there is no increase in the activity of substance P in the presence of both drugs.

    6. Depolarization with veratridine completely blocked the increase of substance P

      Explants were depolarized with veratridine leading to a decrease in the levels of substance P.

    7. In culture, the (now denervated) adult ganglia exhibited a tenfold rise in substance P, mimicking the increase in neonatal ganglia

      Explants from superior cervical ganglia were obtained to address the question: is there transmitter plasticity in mature neurons? Explants were obtained from rats of age six months and one year. A ten-fold increase was observed in the activity of substance P.

    8. chlorisondamine

      A drug that blocks the binding of acetylcholine to its nicotinic receptors.

    9. neurogenesis

      Formation of new neurons.

    10. neosynaptogenesis

      Neo- meaning new, synaptogenesis referring to the formation of connections between neurons.

    11. transmitter mutability may constitute a unique mechanism underlying plasticity in the nervous system

      This article describes the work of Spitzer and his colleagues on neurotransmitter switching. The tadpoles in these experiments tends to attach only to its kins.

      However, there is neurotransmitter phenotype change from one to another. The researchers have found a mechanism that helps in regulation of this neurotransmitter phenotype change. The release of the neurotransmitter caused the tadpoles to bond to those who are not biologically related to them. The switching has affected the social bond formation in tadpoles.

      Read more at Dana Foundation.

    12. autoreceptors

      Referring to a case where the neurotransmitter and the receptors are present on the same cell. The released neurotransmitter binds to the receptor on the same cell.

    13. veratridine did not significantly alter TH-positive cell number, suggesting that depolarization increased TH per neuron rather than increasing the number of neurons.

      What could have been the cause of an increase in TH activity? The answers could be one of the two options: increase in the number of TH positive neurons in the sample or increase in the amount of TH per neuron. 

      In other words, is it an individual neuron's effect or a collective effort of all neurons in the sample? To address this, the authors decided to measure the number of TH positive cells in the control and veratridine-treated cultures. 

      The results show that the there is no difference in the number of neurons between both the group. Concluding that, there is an increase in the amount of TH per neuron individually but not in the total number of TH positive neurons.

    14. morphometric analysis

      A quantitative measurement of a neuron size, shape, or density.

    15. depolarizing concentrations of K+ reproduced the effect of veratridine, suggesting that depolarization per se increased TH activity

      Potassium(K+) is used as a depolarizing agent in this study. The depolarization using potassium is expected to behave similarly to the effects observed with veratridine as both the chemicals increase the influx of sodium channels.

      The authors show that, in the presence of potassium, there is approximately 35% increase in TH activity as compared to their controls.

    16. pontine

      Refers to the group of neurons present in the pons of the brain.

      Pons is a brain region that links medulla and the mid-brain. It serves as a message station between several areas of the brain.

    17. this effect was blocked by tetrodotoxin

      Tetrodotoxin is a sodium channel blocker while veratridine activates the influx of sodium. Since these two drugs act opposing to each other, we expect to have no net effect in the cultures. And that’s what was observed in the cultures exposed to veratridine in the presence of tetrodotoxin (see TTX+Ver in figure 4), there is no further effect in the TH activity as compared to their controls.

    18. veratridine depolarization

      Veratridine is a drug that causes an increase in the sodium influx. The authors used the drug to cause depolarization.

    19. These observations suggest that membrane depolarization and associated transmembrane Na+ influx decrease [Leu]enkephalin in adult medulla

      Decrease in [leu]enkephalin in adrenal medulla is dependent on two related factors: Membrane depolarization and the sodium influx through the membranes.

    20. S.E.

      Stands for standard error, a measure to test how far the mean of the sample is different from the estimated mean of the population.

    21. In contrast, 4-day adult explants revealed a marked increase in proenkephalin mRNA, which paralleled the rise in [Leu]enkephalin

      At four days, mRNA of proenkephalin showed a greater increase similar to the increase observed in [leu]enkephalin in medullary explants.

    22. histofluorescence

      Fluorescent markers are used to label catecholamine in the neurons and visualized using a fluorescent microscopy.

    23. unmanipulated

      No change; unaltered.

    24. nicotinic receptors

      These are receptors that respond to the neurotransmitter, acetylcholine.

    25. Control

      These are explants obtained from nucleus locus ceruleus. These explants are placed in nutrient medium and no drugs are provided to this group. This group serve as a comparison group to the groups treated with the drugs.

    26. J. E. Adler and I. B. Black, Science, in press

      Given that the plasticity occurs during development, the authors tested whether the plasticity can be observed in mature neurons as well. The authors performed these experiments in ganglia of young and old rats and assessed the changes in neurotransmitter, substance P.

      The substance P had a significant increase in expression at young age and at six months of age but not two-year old rats.

    27. explanted superior cervical ganglia

      The ganglia was removed from the animal and transferred to a nutrient medium. These explants were maintained in the medium for six months to one year. At several time points, the explants were taken and observed for the activity of substance P.

    28. a ganglionic blocking agent that prevents depolarization by competing with acetylcholine for postsynaptic nicotinic receptors, reproduced the effects of denervation

      Using a blocking agent for nicotinic receptors, the binding of acetylcholine was blocked in the ganglia. This manipulation is similar to denervation technique and hence, the authors observed an increase in the activity of substance P.

    29. pituitary-adrenal axis

      Refers to the connections and interactions between the pituitary gland and adrenal glands. 

    30. progenitors

      Precursors.

    31. neurohumoral products

      Neuroendocrine cells are the cells that receive input from neurons and release a hormone into blood for output. Any hormone produced and released by neuroendocrine cells are referred as neurohumoral products.

    32. tetrodotoxin

      Sodium channel blocker. It blocks the influx of sodium into the cell.

    33. influx

      Act of flowing in.

      Example: An influx of tourists was observed over the holidays.

    34. VIP (vasoactive intestinal polypeptide)

      A neurotransmitter that can be released from exocrine glands; for instance, sweat glands.

      Functions include relaxation of smooth muscles in stomach, gall bladder, and contraction of heart muscles.

      It has been shown that in sweat glands, both VIP and acetylcholine (or cholingeric) are released from same population of neurons.

    35. catecholaminergic

      Refers to the cell group that releases one of the neurotransmitters, dopamine or norepinephrine.

    36. tyrosine hydroxylase

      An enzyme responsible for the conversion of tyrosine (an amino acid) to dopamine, a neurotransmitter.

    37. the high-affinity uptake system for α-CH3-norepinephrine (5), a characteristic of noradrenergic neurons

      The uptake of norepinephrine in these neurons remain unaffected. The neurons are capable of producing noradrenaline.

    38. Sympathetic neurons innervating rat eccrine sweat glands appear to convert from noradrenergic to cholinergic

      Noradrenergic neurons produce norepinephrine, the neurotransmitter expressed in rat sweat glands during postnatal stages of development. For a short period of time in development, the neurons lose the noradrenergic expression, but pick up the expression of acetylcholine.

    39. quantitative

      Refers to the measurement of quantities, a countable amount of something. For example: A baby weighs 7 pounds and 4 ounces.

    40. qualitative

      Refers to the measurement of qualities, a describable trait of something. For example: The girl has brown eyes.

    41. phenotype

      Here, referring to the physical characteristics of the neurons.

    42. Consequently, neurons may respond to environmental information by altering transmitter phenotypic expression and, presumably, the signals sent to other neurons.

      Since this paper was published in 1984, the field of synaptic plasticity has progressed. This NeuWire article, is an example to show that, in response to environmental conditions (such as changes in day length), the neurotransmitter switches. This change in neurotransmitter release also has an impact on behavior in these animals.

      See the original research in Science in the "Related Content" tab and here.

    43. may change transmitter status during development and maturity, upsetting the tacitly assumed dogma of transmitter immutability, and adding an entirely new dimension to our appreciation of neural plasticity.

      When this paper was published, it was assumed that each neuron produces only one transmitter, however more recent research has challenged this assertion. Contrary to traditional teaching, this article summarizes the new findings in the field of neurotransmitter plasticity. Some of which include mechanisms of neurotransmitter plasticity, mechanisms of neurotransmitter switching, and their impact in neurological disorders.

      Read more at Jon Lieff MD: http://jonlieffmd.com/blog/new-type-of-neuroplasticity-involving-changes-in-neurotransmitters

    44. peptide putative transmitters

      Widely accepted class of neurotransmitters.

      Read more about the different neurotransmitters here.

    45. Neurotransmitters

      A chemical that is released by brain cells called neurons. These chemicals aid in communication or passing messages between neurons.

    46. veratridine

      Drug that increases the influx of sodium into the cell.

    47. mutability

      The ability to change.

      For example, think of a caterpillar, which has the ability to change to butterfly.

    48. thermoregulation

      Maintaining the body’s temperature within the normal limits.

    49. vegetative functions

      Functions of the body that are essential for life–e.g. sleeping, eating, breathing, bladder activity.

    50. peptide transmitters

      These are a class of neurotransmitters. Peptides are made of amino acids or chain of amino acids.

      Read more about the different neurotransmitters here.

    51. regulation

      Set of codes that helps the organism to adapt and maintain life. 

      In this instance, regulation occurs at the gene level to adapt to environmental conditions.

    52. transcriptional level

      A regulation that controls the conversion of DNA to RNA in organisms. Learn more with this HHMI BioInteractive video.

    53. basal

      Normal or minimum level.

    1. translational

      Research that can be useful to prevent or treat disease

    2. developmental

      Relating to the growth of the individual.

    3. subsequent

      Following.

    4. cocaine-induced

      The response prompted by cocaine.

    5. nicotine-induced

      Response prompted by nicotine.

    6. risk

      Prone to; susceptible.

    7. pretreatment

      Treatment received prior to something in advance

    8. assessed

      Evaluate; measure.

    9. administered

      Given.

    10. prompted

      Pushed; urged; required.

    11. diminished

      Reduced.

    12. Locomotor sensitization

      A technique used to measure the movement or locomotor activity of the animal assessed in the open field box. It is thought that with repeated administration of the drug, the animals can show an increase in locomotor activity, which is a sign of sensitization.

      Photobeams are placed on the walls of the box to record the movements of the animal. The mice can explore and get used to the test area of the open field.

      The animal is tracked for the distance covered in centimeters using an automated video system. The experiment is repeated on day 1 and on each day following the injection of cocaine (on days 8, 9, 10, 11). The total distance covered by the animal is recorded for each day.

      Watch the technique here at: https://www.jove.com/video/53107/assessment-cocaine-induced-behavioral-sensitization-conditioned-place

    13. CPP measures an animal’s preference for a particular place in its environment, which develops as that place becomes consistently associated with a rewarding stimulus and assumes some of the rewarding effects of the stimulus

      A three-chamber apparatus is constructed with access to two chambers for the animal for this experiment. There are 3 phases to this experiment: pre-conditioning, conditioning, and testing.

      Pre-conditioning: Animal can freely move on any side of the chamber. For each animal, the first preference of the chamber is noted. This was done on days 7 and 8 of the experimental protocol.

      Conditioning: Train the animals to saline on its preferred chamber and to cocaine on the least preferred side. This was done on days 9, 10, and 11 of the experimental protocol.

      Testing: On day 12 of the experiment, the animals are allowed to have access to both sides of the chamber for 30 minutes. The time spent in the preferred chamber and the less preferred chamber is recorded.

      View the video to learn more about the conditioned place preference protocol. The protocol is describing how to measure craving in animals using morphine as the drug of preference. https://www.jove.com/video/58384/a-conditioned-place-preference-protocol-for-measuring-incubation

    14. endpoints

      Outcome

    15. long-term synaptic potentiation

      Strengthening of synapses between neurons

    16. long-term potentiation

      Slice electrophysiology is a technique that is widely used to study synaptic plasticity. Brain slices containing the nucleus accumbens region was obtained from the mice.

      For this technique, stimulating and recording electrodes are needed. Recording electrodes measure the electrical activity of the neurons in the area. Stimulating electrodes are used to stimulate a dendrite (s) in the brain region that can elicit a response which can be recorded via the recording electrode. The stimulus is given at a rate of 1 per minute.

      The stimulating electrode was placed in the nucleus accumbens, and the recording electrode was placed near to the stimulating electrodes.

      The amplitude or the size of the response can be calculated from each stimulus. Baseline values were obtained. After that, an LTP stimulus was given, and the post-LTP data was collected. The data were normalized to baseline values.

      Watch the video here on LTP is done in hippocampus, a brain region involved in memory: https://www.jove.com/video/2330/preparation-acute-hippocampal-slices-from-rats-transgenic-mice-for

    17. high-frequency stimulation

      The neurons are activated by a high frequency of 100Hz. The protocol used here: 4 trains of 100 Hz tetanus 3 mins apart and are represented below:

    18. FosB expression

      Chromatin immunoprecipitation technique is used to measure FosB expression.

      Briefly, the brain tissue was fixed with formaldehyde to crosslink the DNA binding proteins. The DNA was sheared into small fragments, some of which contains the DNA binding proteins. Using specific antibodies (H4, H3), the DNA binding protein complex was isolated. The proteins are digested, and the DNA is released. The specific DNA sequences of interest were amplified to see if they precipitated with the antibody.

      Watch the video here: https://www.jove.com/science-education/5551/chromatin-immunoprecipitation

    19. PCR

      mRNA was isolated from the brain tissue using the Trizol reagent. RNA was later reverse transcribed to cDNA or complementary DNA using primers of interest. The fold difference of mRNA over control values is calculated and compared across the groups.

      Check the video here on the technique: https://www.youtube.com/watch?v=0MJIbrS4fbQ

    20. Immunoblots

      Protein was extracted from the tissue. Proteins are separated based on molecular weights in a SDS-Page gel. The gel was transferred to nitrocellulose membrane.

      The antibodies to H3 and H4 were applied to the membrane to detect the bands of interest.

      Watch the technique here: https://www.jove.com/science-education/5065/the-western-blot

    21. SAHA

      The drug was administered directly to the nucleus accumbens of the mice.

      In order to do so, the coordinates of the nucleus accumbens are obtained from the mouse brain atlas. The mouse is placed in a stereotaxic chamber, and the cannula was inserted into the brain to inject the drug every day for 7 days. The cannula was guided to be inserted into the brain using the coordinates

    22. HDAC activity

      The nuclear fractions are obtained from the mice using a nuclear extraction kit. HDAC activity was measured using the kit.

  2. Jun 2019
    1. prenatal

      before birth; during pregnancy

    2. phenocopied

      mimicked; acted similarly

    3. transient

      only for a short time

    4. baseline

      normal

    5. facilitation

      help; make the process easy

    6. variant

      modified

    7. ERK/MAPK

      signaling pathways that help in gene regulation

    8. phosphorylates

      adding phosphate residues

    9. concurrent

      happening at the same time

    10. Hypoacetylated

      not enough acetylation

    11. deacetylase

      removal of acetyl groups

    12. hyperacetylation

      increase or excessive acetylation

    13. promoter

      DNA sequences that define where the transcription should start in a gene

    14. disinhibits

      restrain

    15. simulate

      prompt or trigger

    16. psychostimulants

      drugs that cause an increased behavioral or motor response

    17. robust

      widely used

    18. behavioral paradigm

      a model designed to perform behavioral experiments

    19. acetylation

      Process by which acetyl groups are added to preferred residues in a protein.

      For instance, acetyl groups are added to lysine residues in a protein structure

    20. histone

      components of chromatin that helps in gene regulation

    21. chromatin

      DNA + histone

    22. FosB

      it is one of the transcription factors that help in gene expression

    23. transcription

      the process by which a copy of genetic information is made from DNA to RNA

    24. synaptic

      A synapse is a space between the neurons that allows passage of electric or chemical signals between the neurons.

      Anything that occurs between synapses is referred to as synaptic

    25. plasticity

      the ability of the neurons (brain cells) to change and learn new things by changing their synaptic strength

    26. spiny neurons

      Medium sized neurons that have dendritic branches

    27. inhibitory

      slowing down, hold back, restrain, negatively affecting a response

    28. GABAergic

      neurons that contain inhibitory neurotransmitter, GABA

    29. prefrontal cortex

      Part of the frontal cortex in the brain. Its function includes planning, organization, and decision making

    30. amygdala

      A brain region present in the temporal lobe. It is almond In shape. It plays an important role in emotions.

      Eg. When we see a lion, we immediately run due to fear. The fear response is due to the amygdala.

    31. ventral tegmental area

      A brain region in the midbrain. Serves as a center for the origin of dopaminergic neurons

    32. glutamatergic

      neurons that can modulate (or alter or modify) the neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter

    33. dopaminergic

      neurons that contain neurotransmitter, dopamine. Dopamine plays a vital role in the reward pathway

    34. integration

      to combine the similarities together

    35. convergence

      bringing together two different concepts that share similarities

    36. reward

      recognition of one’s work or effort

    37. ventral striatum

      contains the brain region, nucleus accumbens

    38. nucleus accumbens

      A brain region in the forebrain. It has two parts: core and shell

    39. addictive

      causing someone to become dependent

    40. cocaine

      Recreational drug. Referred as coke.

    41. nicotine

      primary chemical present in tobacco

    42. addiction

      dependency, craving

    43. modulated

      modify

    44. enhanced

      increased

    45. place preference

      preferred choice of one place over another

    46. conditioned

      trained or habituated

    47. sensitization

      Repeated administration of a stimulus can cause a response to the stimulus.

      Eg. If you give your cat piping hot milk the first day, the cat may not drink it as it will burn its mouth. However, if you continue to give your cat hot milk for several days in a row, the cat will eventually start drinking the milk as it is habituated to the new stimulus (hot milk) and will not complain

    48. Locomotor

      the movement of a living being from one place to another

    49. sequential

      one by one; logical order

    50. determinant

      a key factor

    51. irrelevant

      not important

    52. molecular genetic

      study of the structure and function of genes involved in the behavior

    53. electrophysiological

      observing the electrical properties of neurons in the mouse brain

    54. behavioral

      observing the behavior of the mouse

    55. exert

      influence

    56. gateway drugs

      the substances are mild and not addictive on consumption. However, the continuous consumption of these mild substances can lead to the use of other addictive drugs. They are also known as ‘habit-forming drug.’

      Eg. Alcohol, Cigarettes.

    57. epidemiological

      Deals with incidence and distribution of diseases and societal issues

    58. illicit drug

      Substances that are addictive to the central nervous system.

      These substances are illegal to be possessed, have no documented therapeutic effect, and are referred to as drugs of abuse.

      Eg. Cocaine, Heroin

    59. marijuana

      ‘weed’ or ‘pot.’

      Read more about marijuana here: https://www.drugabuse.gov/publications/research-reports/marijuana/what-marijuana

    60. Similarly, the expression of FosB after cocaine administration was the same in mice exposed to nicotine 14 days earlier and in mice without previous nicotine exposure

      In contrast to the results we obtained with 7 days of nicotine treatment paired with cocaine, these animals did not show any change in the magnitude of LTP, no increase in locomotor activity of in FosB gene expression.

      This indicates that the priming effect of nicotine can occur only when the drugs are given in a close window and not otherwise.

    61. 14 days after stopping 7 days of nicotine treatment

      The mice receive 7 days of nicotine or water, and then the animals are weaned off the drug for 14 days. Cocaine was administered to animals after day 14 of treatment.

    62. To investigate further the duration of the priming effect of nicotine

      What is the duration of nicotine exposure that is needed to obtain the priming response we see in these animals?

      Does nicotine need to be given closer to another drug or separated a few days apart?

    63. Theophylline-treated mice also showed a reduction in levels of acetylated histone H4

      A reduction in acetylated levels of histone H4 was observed

    64. The acetylated chromatin induced by nicotine exposure would then allow greater FosB gene expression in response to cocaine injection than FosB gene expression after cocaine alone.

      Figures 5 and 6 suggest that the nicotine inhibits HDAC activity, thereby causing global acetylation in the striatum and affecting gene expression.

      In response to cocaine, this acetylation is further enhanced, thus allowing a more significant response in gene expression.

    65. exhibited no increase in FosB mRNA expression in response to cocaine, although cocaine alone increased FosB expression by 176%

      FosB gene expression is also reduced in mice treated with theophylline and cocaine compared to theophylline alone.

    66. Both groups showed a comparable increase in LTP. However, the theophylline-treated mice exhibited an attenuated LTP reduction in response to cocaine treatment

      As expected, in LTP experiments, the mice treated with theophylline and cocaine injections showed a decrease in the magnitude of LTP compared to mice treated with theophylline alone.

    67. To test further the idea that histone acetylation and deacetylation are key molecular mechanisms for the effect of nicotine on the response to cocaine, we conducted two sets of experiments, one genetic and one pharmacological

      Next, the authors tested the idea of histone acetylation by using a low dosage of theophylline, an HDAC stimulator. In contrast to SAHA, the theophylline should decrease the response to cocaine.

    68. Similar to nicotine alone, SAHA alone did not cause a depression in LTP

      SAHA alone did not impair LTP just like nicotine did not impair LTP.

    69. SAHA pretreatment fully simulated nicotine pretreatment and induced a greater reduction in LTP in the core of the NAc than did cocaine alone

      Pretreatment with SAHA followed by cocaine caused a dramatic decrease in the magnitude of LTP response at 180 mins. These results suggest that nicotine does inhibit HDAC activity.

    70. we found that a single cocaine injection after local pretreatment with SAHA for 7 days resulted in 142% more FosB mRNA expression than without pretreatment with SAHA

      Further, when SAHA was infused into nuclear accumbens for 7 days followed by cocaine injection, the FosB expression levels and acetylation of histone residues in striatum increased than the pretreatment with SAHA.

    71. observed a 71% increase in FosB expression in the pretreated mice compared to mice treated with cocaine alone

      Similar to nicotine, SAHA increased the FosB expression levels by 71% and caused acetylation of histone residues in the striatum.

    72. we asked whether we could simulate the effect of nicotine by specifically inhibiting deacetylases with the HDAC inhibitor suberoylanilide hydroxamine acid

      If nicotine is inhibiting HDAC activity, then by using an HDAC inhibitor, we should be able to mimic the effects of nicotine on LTP and FosB expression. This hypothesis was tested by using SAHA, an HDAC inhibitor.

    73. there was a 28% reduction in HDAC of mice treated for 7 to 10 days with nicotine

      28% reduction in HDAC activity was measured in animals treated with nicotine, suggesting that the nicotine inhibits the HDAC activity, thereby decreasing deacetylase activity.

    74. histone deacetylase (HDAC) activity directly in the nuclear fraction of cells in the striatum

      To confirm that, histone deacetylase activity (HDAC) was measured in the striatum.

    75. Does the hyperacetylation produced by nicotine result from activation of one or more acetylases or from the inhibition of deacetylases?

      The authors next addressed whether the acetylation of residues is due to an increase in activation of acetylases or due to inhibition of deacetylase.

    76. 7 days of nicotine treatment (10 μg/ml) increased histone H3 and H4 acetylation by 32 and 61% in the whole striatum, compared with controls treated with water, much as it did at the FosB promoter

      Again, there was an increase in acetylation levels of H3 and H4 in the striatum.

      These results suggest that the nicotine increases the effect of cocaine on FosB expression by increasing the acetylated residues in FosB, thereby enhancing chromatin reorganization.

    77. we used immunoblotting and examined the extent of chromatin modifications in the whole striatum of mice chronically treated with nicotine

      The authors observed the acetylation levels of H3 and H4 after 7 days of nicotine treatment in striatum tissue using chromatin immunoprecipitation and immunoblotting.

    78. We found that, after 7 days of nicotine treatment (10 μg/ml), acetylation of both histone H3 and histone H4 was increased by 34 and 39%, respectively

      Authors observed the acetylation of histone H3 and H4. It is shown that both H3 and H4 got acetylated after a single dose of cocaine injection and after nicotine pretreatment.

    79. whether nicotine enhances FosB expression in the striatum by altering chromatin structure at the FosB promoter and, if so, does it magnify the effect of cocaine?

      The authors asked the question: does nicotine increase FosB expression by altering the chromatin structure at FosB promoter?

    80. The effects on FosB expression are unidirectional; nicotine primes the cocaine response, but cocaine does not prime the nicotine response

      This suggests that the nicotine precedes cocaine and not in the reverse order.

    81. We found that 7 days of cocaine treatment blunted rather than amplified the effect of nicotine on FosB expression in the striatum when compared to the response to nicotine alone.

      On the contrary, the increase in FosB expression we observed in nicotine pretreatment is entirely absent with the cocaine pretreated animals.

    82. we gave cocaine (30 mg/kg) in two protocols: for 24 hours or 7 consecutive days followed by 24 hours of treatment with nicotine

      The animals were given cocaine in drinking water for 7 days. Later, the mice were administered nicotine for 4 days. FosB mRNA levels were measured.

    83. does nicotine pretreatment followed by cocaine increase the response to cocaine, whereas the reverse order of drug treatment does not?

      These experiments were performed to determine if the nicotine pretreatment combined with cocaine injection produces similar results to cocaine pretreatment combined with nicotine injection.

    84. Chronic nicotine administration produces changes in gene expression in the brain so that, after nicotine, the brain responds differently to cocaine with respect to long-term synaptic changes

      It could be that the nicotine causes a gene expression in animals. This primed response serves as a precursor for the brain to respond differently to cocaine to produce long term plasticity changes.

    85. As in the behavioral and physiological experiments, 24 hours of nicotine pretreatment produced quite different results from the 7-day treatment and did not lead to an increased FosB response to cocaine

      On the contrary, FosB expression was increased only in animals that received a cocaine injection after 7 days of nicotine treatment and not in 24 hours of treatment.

      This suggests that the long term nicotine effect is responsible for the changes in gene expression.

    86. we found that both 24 hours and 7 days of administration of nicotine (10 μg/mg) in the drinking water caused 50 and 61% increases in FosB expression

      Both 24 hours and 7 days of nicotine administration caused an increase in FosB expression by 50% and 61%.

    87. Treatment with cocaine alone for 7 days or cocaine treatment for 7 days followed by 24 hours of nicotine treatment did not alter LTP

      However, mice treated with cocaine show a 17% decrease in the observed LTP.

    88. The reduction started immediately after the high-frequency stimulation (HFS) and persisted for up to 180 min compared with cocaine alone

      In this experiment, the authors wanted to determine if the sequential drug use of cocaine can alter the cocaine-induced synaptic plasticity.

      After high-frequency stimulation (HFS), mice treated with nicotine alone or water exhibit LTP that lasts for 180 mins. Mice pretreated with nicotine combined with cocaine injection show a dramatic reduction (~40%) in the observed LTP.

      This suggests that the changes in LTP in nucleus accumbens is caused by pre-exposure of nicotine to the mouse.

    89. In brain slices taken from the striatum, we measured LTP in the excitatory synapses (in the cortico-accumbens pathway) in the NAc core (Fig. 2A), known to be reduced in response to chronic cocaine administration

      Cocaine is capable of producing LTP in several brain regions.

    90. We found that the rate of cocaine dependence was the highest among cocaine users who initiated cocaine after having smoked cigarettes

      Similar to the results obtained from animals, the individuals who started using cocaine were also active smokers, i.e., they initiated cocaine after smoking.

    91. mice pretreated with nicotine showed a 78% further increase in preference for the cocaine-coupled chamber compared with mice treated only with cocaine, with no previous exposure to nicotine

      Mice pretreated with nicotine coupled with cocaine injections showed a further 78% increase in preference to cocaine-coupled chamber than cocaine-treated animals.

      This suggests that persistent treatment of nicotine for 7 days increases the locomotor activity and behavioral responses of the animals

    92. Cocaine alone increased place preference by 223% compared with saline control

      The experiment was performed to determine the behavioral response in the 4 groups of animals.

      Do these animals have a conditioned place preference or aversion to cocaine? If the place preference to cocaine exists, which group out of 4 show the most sensitization to the CPP?

      In the conditioned place preference test, mice pretreated with cocaine alone showed preference to the cocaine-coupled chamber by 223%.

    93. Mice treated with nicotine for 7 days followed by cocaine showed a significant enhancement of 98% in locomotor activity compared with mice treated with cocaine alone

      Mice treated with nicotine for 7 days, followed by cocaine for 4 days show a 98% increase in locomotor activity than the control mice

    94. Mice treated only with cocaine showed a 58% increase in locomotion (sensitization) compared with controls

      Mice treated with an injection of cocaine for 4 days show a 58% increase in locomotor activity than the control mice

    95. Mice treated with nicotine (50 μg/ml) showed the same levels of locomotion (that is, no increase in locomotion compared to day 1) as water controls.

      There is no difference in the distance traveled by the animals that were treated with nicotine in drinking water versus drinking water. (yellow vs. black bars, fig 1A).

    96. We treated mice with nicotine (50 μg/ml) in the drinking water for either 24 hours (Fig. 1A) or 7 days

      Nicotine was added to the drinking water for the mice.

      7 days treatment: The mice were fed with the nicotine-containing water for 7 days. For the next 4 days, mice received a cocaine injection intraperitoneally (injection into a body cavity) with continuous exposure to nicotine-containing water. The injections were given once per day.

      24 hours of treatment. The mice were exposed to the nicotine-containing water for 24 hours, and the next 4 days; the mice received a cocaine injection (once per day) intraperitoneally with continuous exposure to nicotine-containing water.

    97. This result is consistent with our earlier finding that SAHA caused a marked increase in FosB expression when given before an acute cocaine injection compared with the effect of cocaine alone

      Similar to nicotine, SAHA also causes an increase in the expression levels of FosB

    98. SAHA helps restore some of the memory deficits in these mice

      In cocaine-treated animals, LTP is impaired. SAHA helped in rescuing certain aspects of LTP in cocaine-treated animals.

    99. Thus, most cocaine users smoked cigarettes before they started using cocaine, and, in addition, they started using cocaine while they were actively smoking cigarettes

      This study shows that the key determinants for sequential drug use are the onset of age and the frequency of drug usage

    100. Because an important step in the molecular sequence leading to the expression of the addictive phenotype in mice is increased FosB expression in the striatum

      The authors use DNA expression array techniques to identify genes that are modified by drugs of abuse and their mechanism of action.

      FosB is shown to regulate gene expression in cocaine-treated animals.

    101. The addiction process is also mediated through histone acetylation of the promoter of the transcription factor ΔFosB

      CBP is instructed to FosB promoter to acetylate H4 histones, thereby regulating the expression of FosB gene in cocaine-treated animals

    102. An acute cocaine injection increases acetylation of histone H4 but not H3 at the FosB promoter

      This paper shows that chromatin remodeling is a key mechanism that contributes to cocaine-induced synaptic plasticity.

      Here the authors show that the cocaine can cause acetylation of histones via histone acetyl transferase (HAT) at a particular promoter site leading to chromatin acetylation and remodeling.

    103. the consequent activation of a downstream cascade of gene expression initiated by CREB [cyclic adenosine 3′,5′-monophosphate (cAMP) response element–binding protein]. This cascade is dependent upon the acetylation of histone tails by the CREB-binding protein (CBP), a histone acetyl transferase (HAT)

      The authors show that the impairment in LTP and chromatin acetylation was observed in the animals.

      By manipulating the CREB binding protein (CBP), some of these deficits were able to be restored. This suggests that LTP depends on the regulation of CBP.

    104. The molecular pathways involved in addiction share some of the same molecular logic and even some of the same molecular steps encountered in long-term memory storage

      Cocaine induces long term depression (LTD), a form of synaptic plasticity in the nucleus accumbens. This impairment in LTD causes deficits in the memory storage in this brain region.

    105. Reduction of excitatory input to the NAc is thought to decrease inhibitory output from the NAc to the VTA and thereby contribute, through disinhibition, to the increased reward and enhanced locomotion activation observed after cocaine administration

      After administering cocaine to animals, there is a decreased excitatory input from the prefrontal cortex to Nucleus accumbens.

      This change in inputs leads to a lack of restraint on the inhibitory output from the nucleus accumbens to the ventral tegmental area, as the inhibitory output remains the same.

      This leads to increased dopaminergic activity in VTA, leading to an increase in motor activity and in reward pathways.

    106. For example, in 2009 in the United States (4), among adults aged 18 to 34 who had used cocaine at least once, 90.4% had smoked cigarettes before they began to use cocaine, 4.7% began using both drugs at the same age, 2.4% used cocaine first, and 2.5% had never smoked

      This survey was conducted in the US to identify the usage and correlation of drugs of abuse. Questions were provided as a survey to the participating individuals, and the results are summarized in the report.

      Examples of queries are age, drug usage, and frequency, lifestyle, smoking, and drinking frequency.

    107. Accumulation of this transcription factor is a crucial step in the establishment of addiction to most drugs of abuse and has been used as a molecular marker for these processes.

      The study has identified genetic changes that occur in mice treated with cocaine.

      Read the summary of research findings in Science Daily: https://www.sciencedaily.com/releases/2018/05/180531102706.htm

    108. In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine, or other illicit substances
    109. Is the hyperacetylation produced by nicotine also a molecular explanation of drug action shared by the two other gateway drugs, alcohol and marijuana?

      Prolonged use of alcohol, another gateway drug also leads to repetitive use of cocaine.

      Read the summary of the research findings in Technology Networks:

      https://www.technologynetworks.com/neuroscience/articles/alcohol-is-gateway-drug-to-compulsive-cocaine-use-293850

    110. Our results showing how nicotine may act as a gateway drug on the brain—an effect likely to occur whether nicotine exposure is from smoked, passive, or nonsmoked forms—emphasize the need for developing more effective public health prevention programs for all products that contain nicotine, especially those targeted toward young people

      The idea and formulation of the gateway hypothesis and how the hypothesis can be tested in animals are explained in the special article written by Dr.Kandel.

      Read the article “A molecular basis for nicotine as a gateway drug” in the New England Journal of Medicine:

      https://www.nejm.org/doi/full/10.1056/NEJMsa1405092

    111. In the general population of the United States and other Western societies, there is a well-defined sequence of drug usage in which the use of tobacco or alcohol precedes the use of marijuana, which in turn precedes the use of cocaine and other illicit drugs

      The National Institute of Drug Abuse provides the statistics, trends, and the health effects of cocaine.

      Read more in Drug Abuse website: https://www.drugabuse.gov/drugs-abuse/cocaine

    112. D. B. Kandel, Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis (Cambridge Univ. Press, Cambridge, UK, 2002), pp. 3–15

      The book chapter introduces the concept of gateway hypothesis – a model to inform how teenagers initiate and progress in the usage of illicit drugs. The chapter addresses these crucial questions from various fronts – neurobiology, animal studies, and epidemiological studies.

    113. F. E. Pontieri, G. Tanda, F. Orzi, G. Di Chiara, Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382, 255–257 (1996).

      The article addresses a fundamental question: is nicotine a habit-forming drug or an addictive drug? The authors performed experiments in mice and concluded that nicotine shares several biological aspects with the drugs of abuse.

    114. J. A. Kauer, R. C. Malenka, Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8, 844–858 (2007)

      The review presents the available evidence that the drugs of abuse can alter the synaptic plasticity mechanisms in the dopaminergic circuit, the key pathway to processing reward in the brain.

    115. A. Kumar, K. H. Choi, W. Renthal, N. M. Tsankova, D. E. Theobald, H. T. Truong, S. J. Russo, Q. Laplant, T. S. Sasaki, K. N. Whistler, R. L. Neve, D. W. Self, E. J. Nestler, Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005)

      The authors show that the cocaine, a drug of abuse, can activate genes at core histones, which can lead to a restructuring of chromatin. This restructuring could have an effect on long-lasting changes in the animal, for instance, modulating the body movements

    116. A. A. Levine, Z. Guan, A. Barco, S. Xu, E. R. Kandel, J. H. Schwartz, CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 19186–19191 (2005).

      The authors show that the cAMP response element binding protein (CREB)-binding protein (CBP) acetylate histones at the FosB promoter in the mouse striatum, thereby regulating the responses to cocaine.

      The authors confirmed this finding by repeating this experiment in mice lacking a copy of the CBP gene. These mice exhibited a decrease response to cocaine than the animals that had an intact copy of the CBP gene.

  3. Apr 2019
    1. postmitotic neurons

      Mature cells that are not capable of cell division.

      Question that is being addressed here is: Compared to immature/developing neurons, does mature cells have a different machinery (or set of mechanisms) to synthesize RNA and different neurotransmittters?

    2. Depolarizing concentrations of K+

      Learn more about depolarization and action potential here and here.

    3. sympathoadrenal

      Relates to both sympathetic nervous system and the adrenal medulla.

    4. lability

      Ability to change.

    5. neonatal

      Newborn or shortly after birth.

    6. cardiorespiration

      Relates to both cardiac (heart) and respiration (lungs) functions. Helps in the maintenance of oxygen and breathing.

    7. in vivo

      Experiments that are performed in animals or humans.

    8. neurotransmitter plasticity.

      Plasticity can be defined as the ability of the brain to mould and shape in response to experience. The change can be due to either change in the receptors present in the brain or the chemicals itself or the mechanism by which receptors respond to chemicals. 

      Neurotransmitter plasticity refers to changes in neurotransmitters in response to plasticity.

  4. Mar 2019
    1. C. F. Dreyfus, K. A. Markey, M. Goldstein, I. B. Black, Dev. Biol. 97, 48 (1983)

      Dreyfus et al. used locus coeruleus, a region in the brain, to study the neurotransmitter expression in brain. His group was able to show that the catecholamines can be expressed both in culture and in animal making the locus coeruleus an excellent system to study the plasticity in brain.