In Mice, Autism-Like Behavior Connected to Problems Pruning Dendritic Spines

September 11, 2014 · Posted in Neurobiology · Comment 
spines on a dendrite

Spines on a dendrite

Autism spectrum disorders are associated with developmental abnormalities at excitatory synapses. Dendrites, the branched projections of neurons where electrical signals are passed from one cell to the next, are covered in hundreds to thousands of spines that facilitate the synaptic connections with other neurons. These spines are created and also pruned as part of normal learning and development.

Post-mortem examination of the brains of patients with autism spectrum disorders shows increased density of dendritic spines and less pruning in certain neurons in the temporal lobe. These examinations also show impaired mTOR autophagy. MTOR is a protein that plays a role in cell growth and survival. Autophagy is the normal process by which some components of cells are broken down.

A 2014 study by Guomei Tang et al. in the journal Neuron showed that mice that are genetically altered to have overactive mTOR also have reduced dendritic spine pruning, blockade of autophagy, and increased autism-like behaviors. An immunosuppressant drug called rapamycin inhibits mTOR, and treating the mice with this drug corrected the problems with spine pruning and the autism-like behaviors. (This was not true for mice who had been altered to have another type of autophagy.) Normal spine formation was not affected by the restored pruning ability.

Tang et al. concluded that mTOR autophagy plays an important role in dendritic spine pruning, and that restoring neuronal autophagy can correct synaptic abnormalities and restore normative social behavior in mice with hyperactive mTOR.

Thalamus Implicated in Depression-Like Behavior and Resilience to It

September 10, 2014 · Posted in Neurobiology · Comment 


At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Scott Russo described characteristics of rodents who showed depression-like behavior after 10 days of exposure to a larger, more aggressive animal (a phenomenon known as defeat stress). These animals exhibited many behaviors that resembled human depression, including anxiety-like behaviors while navigating a maze; activation of the hypothalamic-pituitary-adrenal axis; circadian rhythm abnormalities; metabolic changes such as glucose intolerance; susceptibility to addiction; anhedonia, a lack of interest in sucrose, sex or intracranial self-stimulation; and profound and permanent social avoidance.

In susceptible animals, Russo found anatomical changes in the GABAergic neurons of the nucleus accumbens (also known as the ventral striatum), including increased numbers of synapses and a greater number of stubby spines on dendrites (the branched projections of neurons where electrical signals are passed from one cell to the next), as well as greater excitability of glutamatergic input, observed as excitatory post-synaptic potentials.

Russo’s attempt to identify these key neurons among the billions of neurons and the 100 to 500 trillion synapses in the brain was like the search for a needle in a haystack, but thinks he found it. The medium spiny neurons of the nucleus accumbens contain GABA and receive synapses from the prefrontal cortex, amygdala, and intralaminar nucleus of the thalamus (ILT), in addition to dopamine inputs from the VTA, and cholinergic, somatostatin, and orexin inputs. Russo found that it was the ILT inputs that conveyed susceptibility to defeat stress, and their presynaptic endings showed increased levels of glutamate transporters (VGLUT-2). Driving the ILT was sufficient to cause the rodents to display the depression-like behaviors, and silencing the ILT during defeat stress prevented the susceptible behaviors (like social avoidance) and promoted resilience.

Methamphetamine Kills Dopamine Neurons in the Midbrain of Mice

July 18, 2014 · Posted in Neurobiology, Risk Factors · Comment 

mice receiving an injection

Epidemiological studies have linked methamphetamine use to risk of Parkinson’s disease, and animal studies of the illicit drug have shown that it harms dopamine neurons. A 2014 study by Sara Ares-Santos et al. in the journal Neuropsychopharmacology compared the effects of repeated low or medium doses to those of a single high dose on mice. Loss of dopaminergic terminals, where dopamine is released, was greatest after three injections of 10mg/kg given at three-hour intervals, followed by three injections of 5 mg/kg at three-hour intervals, and a one-time dose of 30mg/kg. All of the dosages produced similar rates of degeneration of dopamine neurons via necrosis (cell destruction) and apoptosis (cell suicide) in the substantia nigra pars compacta (the part of the brain that degenerates in Parkinson’s disease) and the striata.

Patients with Bipolar Disorder More Creative; Creativity Associated with Worse Functional Connectivity of Brain Regions

May 12, 2014 · Posted in Neurobiology · Comment 

woman paintingWhile bipolar disorder can be a devastating illness, multiple studies indicate it is also associated with high levels of creativity. Researchers T. Su and Y. Kuan compared highly creative and normally creative patients with bipolar disorder to healthy controls with either normal or high creativity in the hopes of clarifying some characteristics of creativity in bipolar disorder. At the 2014 meeting of the International Society for Bipolar Disorders, the researchers reported finding greater creativity in patients with bipolar disorder compared to normal controls, and that high creativity was associated with altered functional connectivity of two regions of the brain: the medial prefrontal cortex and the striatum.

The researchers hope to contribute to treatment solutions that can help patients with bipolar disorder reduce their emotional disturbance without losing their more positive cognitive functions like creativity.

Editor’s Note: Benson et al. found that compared to normal controls, bipolar patients had more positive hyperconnectivity of many brain regions using positron emission tomography (PET) scans with fludeoxyglucose to measure brain activity. Su and Kuan used functional magnetic resonance imaging (fMRI) and found less connectivity of these two regions. How these differences relate to bipolar disorder and its links to creativity remain to be further studied.

Mania-like State Produced in Rats By Kindling the Lateral Hypothalamus

April 25, 2014 · Posted in Neurobiology · Comment 


The lateral hypothalamus is responsible for certain physiological functions (the sleep-wake cycle, appetite, energy expenditure, and sexual functions) that are disrupted during mania. At the 2014 meeting of the International Society for Bipolar Disorders, researcher O. Abulseoud et al. presented evidence that a mania-like state could be produced in rats by “kindling” the lateral hypothalamus with an electrode.

The kindled rats engaged in more motor activity; less rest; more sexual self-stimulation; excessive rearing, feeding, and grooming; and more ethanol consumption. Non-kindled rats (and those kindled in other areas such as the nucleus accumbens shell and the infralimbic cortex) did not engage in this combination of behaviors.

To test the similarity between the mania-like behaviors and human mania, the researchers treated the kindled rats with saline solution, lithium, or valproic acid. Lithium and valproic acid reduced these behaviors significantly compared to the saline solution. These treatments also produced long-term increases in mRNA for certain genes (Per1 and CLOCK) that are dysregulated in people with mania.

This animal model may become useful in future research on manic psychopathology in humans.

Exercise Helps Mice with Spacial Learning

February 6, 2014 · Posted in Current Treatments, Neurochemistry · Comment 

mice exercising

Exercise increases brain-derived neurotrophic factor (BDNF), a protein that protects neurons and is important for learning and memory. In a study of mice who were trained to find objects, sedentary mice could not discriminate between familiar object locations and novel ones 24 hours after receiving weak training, while mice who had voluntarily taken part in exercise over a 3-week period could easily distinguish between these locations after the weak training.

Mice who received sodium butyrate (NaB) after training behaved similarly well to those who had exercised. Sodium butyrate is a histone deacetylase (HDAC) inhibitor, meaning it helps keep acetyl groups on histones, around which DNA is wrapped, making the DNA easier to transcribe. In this case the easy transcription of DNA enables learning under conditions in which it might not usually take place.

Both sodium butyrate and exercise promote learning through their effects on BDNF in the hippocampus. They make the DNA for BDNF easier to transcribe, suggesting that exercise can put the brain in a state of readiness to create new or more lasting memories.

Residue from Nuclear Bomb Testing Shows That Contrary to Earlier Reports, Neurogenesis Occurs in the Brains of Adults

January 27, 2014 · Posted in Neurobiology · Comment 

brainIn 2013 we reported that according to Pasco Rakic, professor of neuroanatomy at Yale University, neurogenesis (the production of new neurons) occurs only in rodents, and not in any significant amount in the brains of adult primates. However, a new carbon-dating procedure shows that the adult human brain does actually continue to create new neurons.

According to an article by Spalding et al. published more recently in the journal Cell, such neuroplasticity occurs to a much greater degree than previously thought. The authors base their research on levels of carbon isotope 14 (14C) that were released into the atmosphere during aboveground nuclear bomb tests between 1945 and 1963. Dividing cells require carbon, so the 14C released into the atmosphere during the era of nuclear testing made its way into the cells of people who were alive at the time. Levels of 14C that were incorporated into the DNA of dividing cells correlate with levels of 14C in the atmosphere at the time the cells divided, and since carbon levels have declined at a predictable rate since the nuclear tests, measuring the 14C in cells can show how old they are.

Spalding et al. show that neurogenesis in humans occurs only in the hippocampus. They found evidence that a subpopulation of hippocampal neurons continually renews itself at a rate of about 700 new neurons per day, while other hippocampal cells are non-renewing. The annual turnover rate of about 1.75% is the same for men and women and declines slightly with age.

The researchers were able to determine that the renewing cells play an important role in certain types of brain function. Long-term potentiation, the process by which learning and memory can occur, depends heavily on new cells produced in the part of the hippocampus knows as the dentate gyrus.

Neurosteroid Allopregnanolone May Improve Bipolar Depression

January 21, 2014 · Posted in Neurochemistry · Comment 

smiling man

Sherman Brown of the University of Texas Southwestern reports that the neurosteroid allopregnanolone has positive effects in bipolar depression. Patients in Brown’s study received doses of 100mg capsules twice daily during the first week, then one capsule in the morning and two capsules in the evening during the second week, and two capsules in the morning and three capsules in the evening during the third week.

Neurosteroids can change the excitability of neurons through their interactions with the neurotransmitters that carry signals from neurons across synapses. Among the various types of neurotransmitters, GABA plays an inhibitory role, while glutamate is responsible for excitability. Allopregnanolone, which is naturally produced in the body, has positive effects on GABA receptors and inhibitory effects on glutamate NMDA receptors, so that it increases the balance of inhibition (GABA) over excitation (glutamate).

How Inflammation Increases Glutamate Overexcitation And Neurotoxicity

January 20, 2014 · Posted in Neurochemistry, Risk Factors · Comment 


Research has shown a link between inflammation and mental illness. Inflammation leads to a series of chemical changes that can overexcite neurons and interfere with the protection of neurons.

Inflammation increases the production of indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme that breaks down the amino acid tryptophan into kynurenic acid and quinolinic acid. They in turn increase glutamate, the main excitatory neurotransmitter, and decrease brain-derived neurotrophic factor (BDNF), which keeps neurons healthy.

Kynurenic acid stimulates microglia, which clean up the central nervous system as a form of immune defense, to produce inflammatory cytokine proteins.

Quinolinic acid directly stimulates glutamate receptors and encourages glutamate release from astrocytes. Quinolinic acid also blocks glutamate removal that would normally occur through reuptake into the astrocytes, leading to more stimulation of extrasynaptic glutamate receptors and decreases in BDNF.

Quinolinic acid’s effects are opposite to those of the antidepressant ketamine, which blocks glutamate NMDA receptors and increases BDNF. When people are given interferon protein for the treatment of cancers, quinolinic acid increases in cerebrospinal fluid, inducing depression. The severity of depression induced is correlated with the patient’s levels of quinolinic acid.

It appears that ketamine has indirect anti-inflammatory effects through its ability to block glutamate receptors and increase BDNF.

Glia Cells Prune Over-Abundant Neurons

January 17, 2014 · Posted in Neurobiology · Comment 


The brain contains neurons, which transmit electrical impulses, and glia, which protect and support neurons. New evidence suggests that some types of glia also play a role in pruning back overabundant neurons that are produced as the brain develops in utero.

Researcher Beth Stevens reports that astrocytes secrete a protein called transforming growth factor beta (TGF-beta). TGF-beta is a cytokine, or regulating protein, that activates brain microglia to initiate a complement cascade (C1 to C3), a series of chemical changes that destroy unnecessary neurons and synapses.

The various proteins involved in a complement cascade are numbered. This complement cascade starts with C1q and is continued by C4, C2, and C3, which initiate phagocytosis (or eating up) of the axon terminals of the underutilized neurons, sparing those that are active.

Inflammation and other changes in glia could cause either deficient or excess pruning of neurons, which has been thought to occur in neuropsychiatric disorders such as autism or schizophrenia.

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