 |
 |
|
|
RESÚMENES JUNIO 2004 |
Basic Neuroscience
DOPAMINE, LEARNING AND MOTIVATION
Nature Reviews Neuroscience 5, 483 -494 (2004)
The
hypothesis that dopamine is important for reward has been proposed in a number
of forms, each of which has been challenged. Normally, rewarding stimuli such
as food, water, lateral hypothalamic brain stimulation and several drugs of
abuse become ineffective as rewards in animals given performance-sparing doses
of dopamine antagonists. Dopamine release in the nucleus accumbens
has been linked to the efficacy of these unconditioned rewards, but dopamine
release in a broader range of structures is implicated in the 'stamping-in' of
memory that attaches motivational importance to otherwise neutral environmental
stimuli.
-
Brain dopamine has been linked to both motor and
motivational functions. Several motivational hypotheses have been challenged
and found inadequate, but it remains clear that dopamine is vital for the
'stamping-in' of stimulus–reward and response–reward associations.
-
Stimulus–reward associations are, in turn, crucial
for the subsequent motivation in a previous-reward situation. Response habits
are triggered by environmental stimuli that have been previously associated
with reward, and the initiation of such response habits is not dependent on
immediate dopamine function. If repeated with dopamine function blocked,
however, the old stimulus–reward associations are extinguished and response
motivation progressively weakens.
-
While the motivational effectiveness of
reward-associated stimuli does not require immediate dopamine function, phasic dopamine elevations can nonetheless amplify stimulus
effectiveness. This amplification is thought to be a dopamine function in the
nucleus accumbens.
-
The role of dopamine in the stamping-in of reward
associations might be much less localized. Dopamine seems to have important
roles in the consolidation of memory in various structures — structures that
are linked to different kinds of learning or to the learning of different
things.
-
A full appreciation of the role of dopamine in
motivation must be on the basis of an understanding of not only the role of
dopamine in immediate behavioural arousal, but also
its role in the learning and memory of learned motivational stimuli.
Intraseptal muscarinic ligands
and galanin: influence on hippocampal
acetylcholine and cognition
E. Elvander, P. A. Schött, J. Sandin, B. Bjelke, J. Kehr, T. Yoshitake and S. O. Ögren
Neuroscience .Volume 126, Issue 3 , 2004, Pages 541-557
The
cholinergic neurons in the septohippocampal
projection are implicated in hippocampal functions
such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide
galanin, co-localized with acetylcholine (ACh) in septohippocampal
cholinergic neurons, and how spatial learning assessed by the Morris water maze
test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal
cholinergic function. To test these hypotheses, compounds were microinjected
into the medial septum and hippocampal ACh release was assessed by microdialysis
probes in the ventral hippocampus of the rat. Blockade of septal
muscarinic transmission by intraseptal
scopolamine increased hippocampal ACh
release suggesting that septal cholinergic neurons
are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol
also increased hippocampal ACh
release. Despite this increase, both scopolamine and carbachol
tended to impair hippocampus-dependent spatial learning. This finding also
suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin
infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting
that septal galanin,
contrary to earlier claims, does not inhibit but excites septohippocampal
cholinergic neurons. Galanin receptor stimulation
combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with
an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal
area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited
range of cholinergic muscarinic transmission may
contribute to optimal hippocampal function, a finding
that has important implications for therapeutic approaches in the treatment of
disorders of memory function.
Rebecca Gittins and Paul J. Harrison
Brain Research .Volume 1013, Issue 2 , 9 July 2004, Pages
212-222
Morphometric alterations in the anterior cingulate cortex (ACC) have been reported in schizophrenia
and mood disorders. Parameters affected include glial
and neuronal density, neuronal size and cortical thickness. Some data, especially
in mood disorders, suggest that the left subgenual
ACC is preferentially involved. Qualitative studies show that the ACC cytoarchitecture is heterogeneous, but there are few
quantitative data. We performed a quantitative morphometric
study of five anatomical levels within the ACC (caudal and rostral
subgenual [area 24b sg], rostral and intermediate supragenual
[area 24b] and caudal supragenual [area 24b′])
in both hemispheres of five normal brains. We measured cortical depth, layer
depths, neuronal density, neuronal size, and glial
density, using the optical disector and nucleator. Relative to the subgenual
ACC, the supragenual ACC was thicker, with a deeper
layer V. Supragenual neurons were substantially
larger in all layers, and were less densely packed in layers V and VI, than subgenual neurons. Glial density,
and the glia to neuron ratio, was higher in supragenual than subgenual ACC.
Only minor differences were seen between left and right ACC, between caudal and
rostral subgenual ACC, and
between the three supragenual levels. These data
complement the qualitative descriptions of the heterogeneity of human ACC cytoarchitecture, connections, and functions, especially
between supragenual and subgenual
regions. Our findings also indicate that care must be taken when selecting ACC
tissue to be used for morphometric studies of
psychiatric disorders, since the normal anatomical variation is of a similar
magnitude as the reported disease-related alterations.
Interaction
between the Amygdala and the Medial Temporal Lobe
Memory System Predicts Better Memory for Emotional Events
Florin Dolcos, Kevin S. LaBar and Roberto Cabeza
Neuron. Volume 42, Issue 5 , 10 June 2004, Pages 855-863
Emotional
events are remembered better than neutral events possibly because the amygdala enhances the function of medial temporal lobe
(MTL) memory system (modulation hypothesis). Although this hypothesis has been
supported by much animal research, evidence from humans has been scarce and
indirect. We investigated this issue using event-related fMRI
during encoding of emotional and neutral pictures. Memory performance after
scanning showed a retention advantage for emotional pictures. Successful
encoding activity in the amygdala and MTL memory
structures was greater and more strongly correlated for emotional than for
neutral pictures. Moreover, a double dissociation was found along the
longitudinal axis of the MTL memory system: activity in anterior regions
predicted memory for emotional items, whereas activity in posterior regions
predicted memory for neutral items. These results provide direct evidence for
the modulation hypothesis in humans and reveal a functional specialization
within the MTL regarding the effects of emotion on memory formation.
Eric R. Prossnitz
Life Sciences .Volume 75, Issue 8 , 9 July 2004, Pages
893-899
G
protein-coupled receptors (GPCRs) represent the
largest family of transmembrane signaling molecules
in the human genome. As such, they interact with numerous intracellular
molecules, which can act either to propagate or curtail signaling from the
receptor. Their primary mode of cellular activation occurs through heterotrimeric G proteins, which in turn can activate a
wide spectrum of effector molecules, including phosphodiesterases, phospholipases,
adenylyl cyclases and ion
channels. Active GPCRs are also the target of G
protein-coupled receptor kinases, which phosphorylate the receptors culminating in the binding of
the protein arrestin. This results in rapid
desensitization through inhibition of G protein binding, as well as novel
mechanisms of cellular activation that involve the scaffolding of cellular kinases to GPCR-arrestin
complexes. Arrestins can also serve to mediate the
internalization of certain GPCRs, a process which
plays an important role in regulating cellular activity both by mediating
long-term desensitization through down regulation (degradation) of receptors
and by recycling desensitized receptors back to the cell surface to initiate
additional rounds of signaling. The mechanisms that regulate the subsequent
intracellular trafficking of GPCRs following
internalization are largely unknown. Recently however, it has become clear that
the pattern of receptor phosphorylation and
subsequent binding of arrestin play a critical role
in the intracellular trafficking of internalized receptors, thereby dictating
the ultimate fate of the receptor. In addition, arrestins
have now been shown to be required for the recycling of GPCRs
that are capable of internalizing through arrestin-independent
mechanisms. This review will summarize recent advances in our understanding of
the roles of arrestins in post-endocytic
GPCR trafficking.
Incongruence between test statistics and P values
in medical papers
Emili Garcia-Berthou and Carles Alcaraz
BMC
Medical Research Methodology 2004, 4:13
Background
Given an
observed test statistic and its degrees of freedom, one may compute the
observed P value with most statistical packages. It is unknown to what extent
test statistics and P values are congruent in published medical papers.
Methods
We
checked the congruence of statistical results reported in all the papers of
volumes 409-412 of Nature (2001) and a random sample of 63 results from volumes
322-323 of BMJ (2001). We also tested whether the frequencies of the last digit
of a sample of 610 test statistics deviated from a uniform distribution (i.e.,
equally probable digits).
Results
11.6%
(21 of 181) and 11.1% (7 of 63) of the statistical results published in Nature
and BMJ respectively during 2001 were incongruent, probably mostly due to
rounding, transcription, or type-setting errors. At least one such error
appeared in 38% and 25% of the papers of Nature and BMJ, respectively. In 12%
of the cases, the significance level might change one or more orders of
magnitude. The frequencies of the last digit of statistics deviated from the
uniform distribution and suggested digit preference in rounding and reporting.
Conclusions
This
incongruence of test statistics and P values is another example that statistical
practice is generally poor, even in the most renowned scientific journals, and
that quality of papers should be more controlled and valued.
Leo P. Sugrue, Greg S. Corrado, William T. Newsome
Science, Vol 304, Issue 5678, 1782-1787 , 18 June 2004
Psychologists
and economists have long appreciated the contribution of reward
history and expectation to decision-making. Yet we know little about
how specific histories of choice and reward lead to an internal
representation of the "value" of possible actions. We
approached this problem through an integrated application of
behavioral, computational, and physiological techniques. Monkeys
were placed in a dynamic foraging environment in which they had to
track the changing values of alternative choices through time. In
this context, the monkeys' foraging behavior provided a window into
their subjective valuation. We found that a simple model based on
reward history can duplicate this behavior and that neurons in the
parietal cortex represent the relative value of competing actions
predicted by this model.
Effect of maprotiline on
Ca2+ movement in human neuroblastoma cells
Shu-Shong Hsu, Wei-Chuan Chen, Yuk-Keung
Lo, Jin-Shiung Cheng, Jeng-Hsien
Yeh, He-Hsing Cheng, Jin-Shyr Chen, Hong-Tai Chang, Bang-Ping Jiann,
Jong-Khing Huang and Chung-Ren
Jan
Life Sciences .Volume 75, Issue 9 , 16 July 2004, Pages
1105-1112
In human
neuroblastoma IMR32 cells, the effect of the
anti-depressant maprotiline on baseline intracellular
Ca2+ concentrations ([Ca2+]i)
was explored by using the Ca2+-sensitive probe fura-2. Maprotiline at concentrations greater than 100 
M
caused a rapid rise in [Ca2+]i
in a concentration-dependent manner (EC50 = 200 M).
Maprotiline-induced [Ca2+]i rise was reduced by 50% by removal of
extracellular Ca2+. Maprotiline-induced
[Ca2+]i rises were inhibited by
half by nifedipine, but was unaffected by verapamil or diiltiazem. In Ca2+-free
medium, thapsigargin, an inhibitor of the endoplasmic
reticulum Ca2+-ATPase, caused a monophasic
[Ca2+]i rise, after which the
increasing effect of maprotiline on [Ca2+]i was abolished. U73122, an inhibitor of phospholipase C, did not affect maprotiline-induced
[Ca2+]i rises. These findings
suggest that in human neuroblastoma cells, maprotiline increases [Ca2+]i
by stimulating extracellular Ca2+ influx and also by causing
intracellular Ca2+ release from the endoplasmic reticulum via a phospholiase C-independent manner.
Prenatal Infection and Risk for Schizophrenia:
IL-1
,
IL-6, and TNF
Inhibit Cortical Neuron Dendrite Development
John H Gilmore1,2, Lars
Fredrik Jarskog1,2, Swarooparani Vadlamudi2
and Jean M Lauder3
Neuropsychopharmacology (2004) 29, 1221-1229
Prenatal
exposure to infection increases risk for schizophrenia, and we have
hypothesized that inflammatory cytokines, generated in response to maternal
infection, alter neuron development and increase risk for schizophrenia. We sought
to study the effect of cytokines generated in response to infection¾interleukin-1 (IL-1), tumor necrosis factor- (TNF), and interleukin-6 (IL-6)¾on the dendritic development of cortical neurons. Primary mixed
neuronal cultures were obtained from E18 rats and exposed to 0, 100, or 1000
units (U)/ml of IL-1, TNF, IL-6, or IL-1+TNF for 44 h. MAP-2-positive neurons were
randomly identified for each condition and the number of primary dendrites,
nodes, and total dendrite length was determined. We found that 100 U of TNF significantly reduced the number of nodes
(27%, p=0.02) and total dendritic length (14%,
p=0.04), but did not affect overall neuron survival. A measure of 100 U IL-1+TNF significantly reduced the number of
primary dendrites (17%, p=0.006), nodes (32%, p=0.001), and total dendritic length (30%, p<0.0001), although it did not
affect overall neuron survival. At 1000 U, each cytokine significantly reduced
the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%); neuron survival was reduced by
14-21%. These results indicate that inflammatory cytokines can significantly
reduce dendrite development and complexity of developing cortical neurons,
consistent with the neuropathology of schizophrenia. These findings also
support the hypothesis that cytokines play a key mechanistic role in the link
between prenatal exposure to infection and risk for schizophrenia.
Effects of Antipsychotic Drugs on Neurogenesis in the Forebrain of the Adult Rat
Hui-Dong Wang, Floyd D Dunnavant,
Tabitha Jarman and Ariel Y Deutch
Neuropsychopharmacology (2004) 29, 1230-1238
The
generation of new cells in the adult mammalian brain may significantly modify pathophysiological processes in neuropsychiatric disorders.
We examined the ability of chronic treatment with the antipsychotic drugs (APDs) olanzapine and haloperidol to increase the number and
survival of newly generated cells in the prefrontal cortex (PFC) and striatal complex of adult male rats. Animals were treated
with olanzapine or haloperidol for 3 weeks and then injected with
5-bromo-2'-deoxyuridine (BrdU) to label mitotic
cells. Half of the animals continued on the same APD for two more weeks after BrdU challenge, with the other half receiving vehicle
during this period. Olanzapine but not haloperidol significantly increased both
the total number and density of BrdU-labeled cells in
the PFC and dorsal striatum; no effect was observed in the nucleus accumbens. Continued olanzapine treatment after the BrdU challenge did not increase the survival of newly
generated cells. The newly generated cells in the PFC did not express the
neuronal marker NeuN. Despite the significant increase
in newly generated cells in the PFC of olanzapine-treated rats, the total
number of these cells is low, suggesting that the therapeutic effects of
atypical APD treatment may not be due to the presence of newly generated cells
that have migrated to the cortex.
Effects of Chronic Fluoxetine
in Animal Models of Anxiety and Depression
Stephanie C Dulawa1,
Kerri A Holick2, Brigitta Gundersen1
and Rene Hen1,2,3
Neuropsychopharmacology (2004) 29, 1321-1330
The
onset of the therapeutic response to antidepressant treatment exhibits a
characteristic delay. Animal models sensitive to chronic, but not acute,
antidepressant treatment are greatly needed for studying antidepressant mechanisms.
We initially assessed four inbred mouse strains for their behavioral response
to chronic treatment with the selective-serotonin reuptake inhibitor fluoxetine (0, 5, 10 mg/kg/day in drinking water), which is
used for the treatment of mood and anxiety disorders. Only the highly anxious
BALB/c strain exhibited sensitivity to fluoxetine in
the forced swim test. Additionally, fluoxetine
reduced locomotion in C57BL/6 and 129SvEv, but not BALB/c and DBA/2, strains.
We then evaluated the effects of subchronic (~4 days)
and chronic (~24 days) fluoxetine treatment (0, 10,
18, 25 mg/kg/day) on measures of anxiety and depression in BALB/c mice. Anxiety
measures were obtained using the open field and novelty-induced hypophagia tests. Antidepressant effects were evaluated
using the forced swim test. We found 18 mg/kg/day of chronic fluoxetine to be active in all three paradigms; subchronic treatment had no effect. Anxiety-related
measures were reduced by 18 mg/kg/day. In the forced swim test, 10 and 18 mg/kg/day
increased swimming and reduced immobility. Here we present several novel
effects of chronic, but not subchronic,
antidepressant treatment.
Fractionating Impulsivity: Contrasting Effects
of Central 5-HT Depletion on Different Measures of Impulsive Behavior
Catharine A Winstanley,
Jeffrey W Dalley, David EH Theobald
and Trevor W Robbins
Neuropsychopharmacology (2004) 29, 1331-1343
Reducing
levels of 5-HT in the central nervous system has been associated with increases
in impulsive behavior. However, the impulsivity construct describes a wide
range of behaviors, including the inability to withhold a response, intolerance
to delay of reward and perseveration of a nonrewarded
response. Although these behaviors are generally studied using instrumental
paradigms, impulsivity may also be reflected in simple Pavlovian
tasks such as autoshaping and conditioned activity.
This experiment aimed to characterize further the effects of central 5-HT
depletion and to investigate whether different behavioral measures of impulsivity
are inter-related, thus validating the construct. Rats received intracerebroventricular (ICV) infusions of vehicle (n=10)
or the serotonergic neurotoxin
5,7-dihydroxytryptamine (n=12) which depleted forebrain 5-HT levels by about
90%. Lesioned animals showed significant increases in
the speed and number of responses made in autoshaping,
increased premature responding on a simple visual attentional
task, enhanced expression of locomotor activity
conditioned to food presentation, yet no change in impulsive choice was
observed, as measured by a delay-discounting paradigm. Significant positive
correlations were found between responses made in autoshaping
and the level of conditioned activity, indicating a possible common basis for
these behaviors, yet no correlations were found between other behavioral
measures. These data strengthen and extend the hypothesis that 5-HT depletion
increases certain types of impulsive responding. However, not all measures of
impulsivity appear to be uniformly affected by 5-HT depletion, or correlate
with each other, supporting the suggestion that impulsivity is not a unitary
construct.
Abnormalities of the NMDA Receptor and
Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar
Disorder
Sarah M Clinton and James H
Meador-Woodruff
Neuropsychopharmacology (2004) 29, 1353-1362
Several lines
of investigation support a hypothesis of glutamatergic
dysfunction in schizophrenia, including our recent reports of altered NMDA
receptor subunit and associated intracellular protein transcripts in the
thalamus of elderly patients with schizophrenia. In the present study, we used
in situ hybridization to measure the expression of NMDA subunits (NR1, NR2A-D),
and associated intracellular proteins (NF-L, PSD95, and SAP102) in a second,
younger cohort from the Stanley Foundation Neuropathology Consortium, which
included patients with both schizophrenia and affective disorders. We wanted to
determine whether glutamatergic abnormalities in the
thalamus in schizophrenia are present at younger ages, and whether these
abnormalities occur in other psychiatric illnesses. In the present work, we
observed increased expression of NMDA NR2B subunit transcripts, and decreased
expression of all three associated postsynaptic density protein transcripts in
schizophrenia. We also found evidence of glutamatergic
dysfunction in the thalamus in affective disorders, particularly in bipolar
disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts
in bipolar disorder, and decreased SAP102 levels in major depression.
Interestingly, one of the most consistent findings across diagnostic groups was
an abnormality of intracellular signaling molecules that are linked to the NMDA
receptor, rather than changes in the receptor subunits themselves. PSD95 and
similar scaffolding molecules link the NMDA receptor with intracellular enzymes
that mediate signaling, and also provide a physical link between different
neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and
other intracellular signaling machinery may contribute to dysregulated
communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic
systems) that are potentially involved in the neurobiology of schizophrenia and
affective disorders.
Association between Catechol-O-Methyltransferase
Functional Polymorphism and Male Suicide Completers
Hisae Ono1, Osamu
Shirakawa1, Hideyuki Nushida2, Yasuhiro Ueno2
and Kiyoshi Maeda1
Neuropsychopharmacology (2004) 29, 1374-1377
Suicide
has been suggested to involve catecholaminergic
dysfunction and to be related to genetics. Catechol-O-methyltransferase
(COMT) 158Val/Met polymorphism (GenBank Accession No.
Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in
catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT
activity, that is, the alleles encoding Val and Met are associated with
relatively high and relatively low COMT activity, respectively. In this study,
we hypothesized that the COMT 158Val/Met polymorphism is associated with
suicide. The study population consisted of 163 suicide completers (112 males
and 51 females). We found that the genotype distribution of the COMT 158Val/Met
polymorphism was significantly different between male suicide completers and
male controls (p=0.036), while the frequency of the Val/Val genotype, a
high-activity COMT genotype, was significantly less in male suicide completers
than in male controls (OR: 0.52; 95% CL: 0.31-0.89; p=0.016). However, this was
not the case in females. Our results suggest that the Val/Val genotype is a
protective factor against suicide in males.
Michaela
Hau, Octavio A. Dominguez
and Henry C. Evrard
Hormones and Behavior .Article in Press
The
hormone testosterone (T) is involved in the control of aggressive behavior in
male vertebrates. T enhances the frequency and intensity of aggressive
behaviors during competitive interactions among males. By promoting
high-intensity aggression, T also increases the risk of injury and presumably
the perception of painful stimuli. However, perception of painful stimuli
during fights could counteract the expression of further aggressive behavior.
We therefore hypothesize that one function of T during aggressive interactions
is to reduce nociception (pain sensitivity). Here, we
experimentally document that T indeed reduces behavioral responsiveness to a
thermal painful stimulus in captive male house sparrows (Passer domesticus). Skin nociception was
quantified by foot immersion into a hot water bath, a benign thermal stimulus.
Males treated with exogenous testosterone left their foot longer in hot water
than control birds. Conversely, males in which the physiological actions of
testosterone were pharmacologically blocked withdrew their foot faster than
control birds. Testosterone might exert its effects on pain sensitivity through
conversion into estradiol in the dorsal horn of the
spinal cord. Decreased nociception during aggressive
encounters may promote the immediate and future willingness of males to engage
in high-intensity fights.
Olivier Raineteau, Lotty Rietschin, Gérard Gradwohl, François Guillemot and Beat H. Gähwiler
Molecular and Cellular Neuroscience .Volume 26, Issue 2 , June 2004, Pages
241-250
A major
challenge in studying neurogenesis in the adult brain
is gaining access to neural stem cells for experimental manipulation. We
developed an approach utilizing mouse hippocampal organotypic cultures to characterize neurogenesis
under controlled conditions. After 2 weeks in culture, double immunostaining using the mitotic marker BrdU
and cell type-specific markers revealed persistent proliferation of various
cell types. The birth of new neurons was restricted to a third subgranular germinal zone as shown by analysis of the
expression pattern of the proneural transcription
factor neurogenin-2 and colocalization of BrdU with neuronal phenotypic markers. The regional
distribution of newly born neurons closely resembled that observed in vivo in
the adult hippocampus. Furthermore, neurogenesis was
increased by chronic application of epidermal growth factor (EGF) and abolished
by adding serum to the culture medium. Our study therefore establishes the hippocampal slice culture as a promising ex vivo model for
investigating neurogenesis.
Altered protein kinase a in brain of learned helpless rats: effects of
acute and repeated stress
Yogesh Dwivedi,
Amal C. Mondal, Pradeep K. Shukla, Hooriyah S. Rizavi and Jennifer
Lyons
Biological Psychiatry .Volume 56, Issue 1 , 1 July 2004, Pages
30-40
Background
Stress-induced
learned helplessness (LH) in animals serves as a model of behavioral depression
and some aspects of posttraumatic stress disorder. We examined whether LH
behavior is associated with alterations in protein kinase
A (PKA), a critical phosphorylating enzyme, how long
these alterations persist after inescapable shock (IS), and whether repetition
of IS prolongs the duration of LH behavior and changes in PKA.
Methods
Rats
were exposed to IS either on day 1 or twice, on day 1 and day 7. Rats were
tested for escape latency on days 2 and 4 after day 1 IS or days 2, 8, and 14
after day 1 and day 7 IS. [3H]cAMP (cyclic
adenosine monophosphate) binding, catalytic activity
and expression of PKA subunits were determined in frontal cortex and
hippocampus.
Results
Higher
escape latencies were observed in rats tested on day 2 after single IS and on
day 14 after repeated IS. Concurrently, reduced [3H]cAMP binding, PKA activity, and expression of selective PKA
RII
and C
and C
subunits were observed in the brains of these rats.
Conclusions
Repeated
IS prolongs the duration of LH behavior, and LH behavior is associated with
reductions in apparent activity and expression of PKA. These reductions in PKA
may be critical in the pathophysiology of depression
and other stress-related disorders.
Elizabeth
M. Quinlan, David Lebel, Inbar
Brosh and Edi Barkai
Neuron.
Volume 41, Issue 2 , 22 January 2004, Pages
185-192
Olfaction
is a principal sensory modality in rodents, and rats quickly learn to
discriminate between odors and to associate odor with reward. Here we show that
such olfactory discrimination (OD) learning consists of two phases with
distinct cellular mechanisms: an initial NMDAR-sensitive phase in which the
animals acquire a successful behavioral strategy (rule learning), followed by
an NMDAR-insensitive phase in which the animals learn to distinguish between
individual odors (pair learning). Rule learning regulates the composition of
synaptic NMDARs in the piriform
cortex, resulting in receptors with a higher complement of the NR2a subunit
protein relative to NR2b. Rule learning also reduces long-term potentiation (LTP) induced by high-frequency stimulation of
the intracortical axons in slices of piriform cortex. As NR2a-containing NMDARs
mediate shorter excitatory postsynaptic currents than those containing NR2b, we
suggest that learning-induced regulation of NMDAR composition constrains
subsequent synaptic plasticity, thereby maintaining the memory encoded by
experience.
Bidirectional
Modification of Presynaptic Neuronal Excitability
Accompanying Spike Timing-Dependent Synaptic Plasticity
Cheng-yu Li, Jiang-teng Lu, Chien-ping Wu, Shu-min Duan and Mu-ming Poo
Neuron. Volume 41, Issue 2 , 22 January 2004, Pages
257-268
Correlated pre- and postsynaptic activity
that induces long-term potentiation is known to
induce a persistent enhancement of the intrinsic excitability of the presynaptic neuron. Here we report that, associated with
the induction of long-term depression in hippocampal
cultures and in somatosensory cortical slices, there
is also a persistent reduction in the excitability of the presynaptic
neuron. This reduction requires postsynaptic Ca2+ elevation and presynaptic PKA- and PKC-dependent modification of
slow-inactivating K+ channels. The bidirectional changes in neuronal
excitability and synaptic efficacy exhibit identical requirements for the
temporal order of pre- and postsynaptic activation but reflect two distinct
aspects of activity-induced modification of neural circuits.
THE AMYGDALA MODULATES THE CONSOLIDATION OF
MEMORIES OF EMOTIONALLY AROUSING EXPERIENCES
James L. McGaugh
Annual Review of Neuroscience.July 2004,
Vol. 27, pp. 1-28
Converging
findings of animal and human studies provide compelling evidence that the amygdala is critically involved in enabling us to acquire
and retain lasting memories of emotional experiences. This review focuses
primarily on the findings of research investigating the role of the amygdala in modulating the consolidation of long-term
memories. Considerable evidence from animal studies investigating the effects
of posttraining systemic or intra-amygdala
infusions of hormones and drugs, as well as selective lesions of specific amygdala nuclei, indicates that (a) the amygdala
mediates the memory-modulating effects of adrenal stress hormones and several
classes of neurotransmitters; (b) the effects are selectively mediated by the basolateral complex of the amygdala
(BLA); (c) the influences involve interactions of several neuromodulatory
systems within the BLA that converge in influencing noradrenergic and muscarinic cholinergic activation; (d) the BLA modulates
memory consolidation via efferents to other brain
regions, including the caudate nucleus, nucleus accumbens,
and cortex; and (e) the BLA modulates the consolidation of memory of many
different kinds of information. The findings of human brain imaging studies are
consistent with those of animal studies in suggesting that activation of the amygdala influences the consolidation of long-term memory;
the degree of activation of the amygdala by emotional
arousal during encoding of emotionally arousing material (either pleasant or
unpleasant) correlates highly with subsequent recall. The activation of neuromodulatory systems affecting the BLA and its
projections to other brain regions involved in processing different kinds of
information plays a key role in enabling emotionally significant experiences to
be well remembered.
DESENSITIZATION OF G PROTEIN-COUPLED
RECEPTORS AND NEURONAL FUNCTIONS
Raul R. Gainetdinov, Richard T.
Premont, Laura M. Bohn, Robert J. Lefkowitz, and Marc
G. Caron
Annual Review of Neuroscience. July
2004, Vol. 27, pp. 107-144
G
protein-coupled receptors (GPCRs) have proven to be
the most highly favorable class of drug targets in modern pharmacology. Over
90% of nonsensory GPCRs are
expressed in the brain, where they play important roles in numerous neuronal
functions. GPCRs can be desensitized following
activation by agonists by becoming phosphorylated by
members of the family of G protein-coupled receptor kinases
(GRKs). Phosphorylated
receptors are then bound by arrestins, which prevent
further stimulation of G proteins and downstream signaling pathways. Discussed
in this review are recent progress in understanding basics of GPCR
desensitization, novel functional roles, patterns of brain expression, and
receptor specificity of GRKs and 
arrestins in major brain functions. In particular,
screening of genetically modified mice lacking individual GRKs
or arrestins for alterations in behavioral and biochemical
responses to cocaine and morphine has revealed a functional specificity in dopamine
and 
-opioid receptor regulation of locomotion and analgesia. An
important and specific role of GRKs and arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential
involvement of these molecules in certain brain disorders, such as addiction,
Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the
utility of a pharmacological strategy aimed at targeting this GPCR
desensitization machinery to regulate brain functions can be envisaged.
THE SYNAPTIC VESICLE CYCLE
Thomas C. Südhof
Annual Review of Neuroscience. July
2004, Vol. 27, pp. 509-547
Neurotransmitter
release is mediated by exocytosis of synaptic
vesicles at the presynaptic active zone of nerve
terminals. To support rapid and repeated rounds of release, synaptic vesicles
undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered
exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the
docking and priming of the vesicles for another round of exo-
and endocytosis. Recent studies have led to a better
definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight
into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular
Ca2+ sensor synaptotagmin 1 triggers fast
release, and how the vesicular Rab3 protein regulates release by binding to the
active zone proteins RIM1
and RIM2
has advanced our understanding of neurotransmitter release. The present review
attempts to relate these molecular data with physiological results in an
emerging view of nerve terminals as macromolecular machines.
HOW THE BRAIN PROCESSES SOCIAL INFORMATION:
Searching for the Social Brain*
Thomas R. Insel and Russell D.
Fernald
Annual Review of Neuroscience. July
2004, Vol. 27, pp. 697-722
Because
information about gender, kin, and social status are essential for reproduction
and survival, it seems likely that specialized neural mechanisms have evolved
to process social information. This review describes recent studies of four
aspects of social information processing: (a) perception of social signals via
the vomeronasal system, (b) formation of social
memory via long-term filial imprinting and short-term recognition, (c)
motivation for parental behavior and pair bonding, and (d) the neural
consequences of social experience. Results from these studies and some recent
functional imaging studies in human subjects begin to define the circuitry of a
"social brain." Such neurodevelopmental
disorders as autism and schizophrenia are characterized by abnormal social
cognition and corresponding deficits in social behavior; thus social
neuroscience offers an important opportunity for translational research with an
impact on public health.
Neuropsychiatric pharmacogenetics:
moving toward a
comprehensive understanding of predicting risks and response
Jeffrey R Bishop; Vicki L Ellingrod
Pharmacogenomics . 2004,
vol. 5, no. 5, pp. 463 - 477
Pharmacogenetic
research in the area of neuropsychiatric illnesses is rapidly evolving. Due to
the complexity of the human brain, it is not surprising that our knowledge
about the interaction between genetics and the treatment of these illnesses is
very small. The Human Genome Project (HGP) has identified > 30,000 genes;
several thousand of which have been found to occur in the brain or serve a role
that enhances the brain's function. Much of the research in the post-HGP era is
being driven by a desire to use genetics to predict which patients deviate from
the norm in terms of drug response or side effects. By identifying these
people, we will be able to direct clinical practice such that therapies for
these disorders can be individualized. With this in mind, the following review
is intended to cover a broad understanding of CNS pharmacogenetics
with the goal of summarizing available literature on promising candidate gene
targets, which may eventually help us predict clinical outcomes in patients
taking medications commonly used to treat neuropsychiatric disorders.