Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана
.pdf
182 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
cortical microcircuits drives symptom expression in affected individuals. Depending
on the brain region affected, shifts in excitation/inhibition balance due to glutamate
and GABA deficits might drive particular mood-related symptoms controlled by each
brain region.
Evidence for Altered Monoaminergic Function
in Mood Disorders
Because many of the drugs used to treat mood-related symptoms modulate monoaminergic function, much research has focused on whether the serotonergic, noradrenergic, and dopaminergic systems are altered in the brains of subjects with mood
disorders. We review some of these studies here.
Serotonergic System
Evidence suggests lower levels of serotonin (5-hydroxytryptamine [5-HT]) and 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT, in the brain stem but not
in the frontal cortex of subjects who died from suicide (Mann et al. 1989). However,
because measuring 5-HT in the postmortem brain is challenging due to cellular and
chemical degradation, most of what is known about serotonergic dysfunction in the
postmortem brain in mood disorders is based on investigation of 5-HT receptor binding and expression (reviewed in Stockmeier 2003 and summarized here). Evidence
suggests higher levels of agonist binding to the postsynaptic 5-HT type 1A (5-HT
receptor in the ventrolateral prefrontal cortex (PFC), but no consistent changes else
where in the PFC or hippocampus, in individuals who died from suicide. Depending
on the methodology used, evidence exists for both higher and lower levels of binding
to 5-HT
als who died from suicide; 5-HT
For the postsynaptic 5-HT
PFC and hippocampus were reported for subjects with MDD as well as for subjects
who died from suicide, with no changes in other regions of the PFC. For the 5-HT
transporter, evidence in subjects who died from suicide, had MDD, or both suggests
lower levels or no differences in binding in cerebral cortex. Studies also suggest no dif
ferences in 5-HT transporter binding in the midbrain dorsal raphe nucleus, pontine
dorsal raphe, medial raphe, or locus coeruleus. Taken together, consistent results suggest higher binding to the 5-HT
receptor in the dorsal PFC in subjects who died from suicide. Because the ventrolateral
and dorsal PFC are both involved in cognition, alterations in serotonergic processes in
subjects who died from suicide might suggest dysfunctional cognitive processes.
autoreceptors in the midbrain dorsal raphe nucleus in depressed individu-
1A
autoreceptors act to inhibit further release of 5-HT.
1A
receptor, higher levels of agonist binding in the dorsal
2A
receptor in the ventrolateral PFC and to the 5-HT
1A
1A
2A
)
-
-
Noradrenergic System
Most noradrenergic neurons originate in the locus coeruleus and project throughout
the brain. In subjects who died from suicide, had MDD, or both, levels of norepinephrine (also known as noradrenaline) were not found to differ across several brain regions, including the brain stem, hypothalamus, frontal cortex, amygdala, and striatum
183 Molecular and Cellular Neurobiology
https://t.me/med1917
(Beskow et al. 1976; Moses and Robins 1975; Pare et al. 1969; Riederer et al. 1980; but
see Arango et al. 1993). However, lower levels of the norepinephrine metabolite me
thoxy-4-hydroxyphenylgycol were reported for some brain regions in subjects with
MDD (Riederer et al. 1980). Related to norepinephrine synthesis, higher levels of tyro
sine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, were reported
in the locus coeruleus of subjects with MDD (Zhu et al. 1999). Levels of the norepi
nephrine transporter, which removes norepinephrine from the synapse, are lower in
the locus coeruleus in subjects with MDD (Klimek et al. 1997). Adrenergic receptor
subtypes have differing effects, with α
stimulatory effect on cell signaling and α
- and β-adrenoreceptors tending to have a
1
-adrenoreceptors tending to inhibit signal-
2
ing. Several studies have examined receptor binding in the brains of subjects with
mood disorders (reviewed in Cottingham and Wang 2012 and summarized with ad
ditional citations here). Higher levels of α
-adrenoreceptor binding were seen in the
1
frontal cortex in subjects who died from suicide, although no such differences were
seen across multiple brain regions in antidepressant-treated subjects who died from
suicide or in the PFC of subjects with MDD (Ferrier et al. 1986).
Findings regarding binding and expression of the α
receptors have also been mixed. Some studies reported higher levels of α
-adrenoreceptor and β-adreno-
2
-adrenore-
2
ceptor in frontal cortex and hippocampus in subjects who died from suicide, had
MDD, or both (Rivero et al. 2014); some studies reported no difference (Ferrier et al.
1986); and one study reported lower levels (Gross-Isseroff et al. 2000). Results for α
2
adrenoreceptor binding in the locus coeruleus appear more consistent, with higher
binding levels both in subjects who died from suicide and in subjects with MDD. For
the β-adrenoreceptors, higher binding levels were reported for β
-adrenoreceptors in
1
the PFC of antidepressant-free subjects with MDD (Rivero et al. 2014), although no
changes in β
- or β2-adrenoreceptors were reported in the hippocampus in subjects
1
with MDD. Thus, with respect to adrenergic receptor subtype binding, results vary
by receptor subtype and brain region, with inconsistent findings across studies. Some
of these discrepancies may be due to methodology or to subject groups examined
(e.g., subjects who died from suicide, subjects with MDD who died from suicide, sub
jects taking or not taking antidepressants). Moving forward, for greater insight into
whether noradrenergic neurotransmission is altered in patients with mood disorders,
future postmortem studies should carefully consider cohort design to disentangle
effects driven by disease, suicide, and/or psychiatric medications.
-
-
-
-
-
-
Dopaminergic System
Amotivation and anhedonia are frequent symptoms of mood disorders. Given that
these are regulated in part by dopamine-related circuits, it is not surprising that re
searchers have asked whether dopaminergic systems are altered in the brains of subjects with mood disorders. Most dopamine-producing neurons are found in brain stem
nuclei, with projections throughout the brain. We summarize findings reviewed in
Dunlop and Nemeroff (2007) and include additional reports. Although evidence suggests that dopamine levels are unaltered across multiple brain regions, including the
brain stem, hypothalamus, and striatum, levels of dopamine metabolites do appear to
be altered. For instance, lower levels of the dopamine metabolite dihydroxyphenylacetic acid were found in the striatum of antidepressant-free subjects with MDD who
-
184 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
died from suicide, and higher levels of the dopamine metabolite homovanillic acid
were found in the frontal cortex of subjects who died from suicide. Lower levels of tyro
sine hydroxylase, the rate-limiting enzyme in catecholamine synthesis, were reported
in the striatum of subjects with MDD who died from suicide (Pizzagalli et al. 2019). For
the dopamine transporter, which is responsible for removing dopamine from the syn
apse, lower levels were found in the striatum (Pizzagalli et al. 2019), and lower levels
of binding were reported for the central and basal nuclei of the amygdala of subjects
with MDD (Klimek et al. 2002). At the dopamine receptor level, no changes in binding
to the dopamine type 1 (D
) receptor (which increases cell signaling) or type 2 (D2) re-
1
ceptor (which decreases cell signaling) were found in the striatum of antidepressantfree subjects with MDD who died from suicide or in the dorsal striatum of subjects who
died from suicide (Fitzgerald et al. 2017). Interestingly, however, although levels of D
and D2 receptor binding are positively correlated in the dorsal striatum in unaffected
comparison subjects, these binding levels are not correlated in subjects who died from
suicide, suggesting dysregulation of these receptors (Fitzgerald et al. 2017). In the
amygdala, higher levels of D
receptor binding were found in the central, basal,
2/D3
and lateral nuclei (Klimek et al. 2002) and higher expression of the dopamine receptor
4 gene DRD4 was reported for the basal nucleus in subjects with MDD (Xiang et al.
2008) (like D
Although D
receptors, D3 and D4 receptors inhibit cell signaling).
2
and D2 binding levels did not differ in the frontal cortex in subjects
1
with mood disorders, investigation of splice variants provides another potential ave
nue for altered dopamine neurotransmission in these disorders. Splice variants are alternative forms of mRNA produced by the same gene; splice variants can produce
different proteins with different functions, even though they are coded for by the same
gene. Subjects with affective disorders exhibit lower expression levels of the dopamine
receptor 2 gene DRD2 short variant (thought to act as a presynaptic autoreceptor) and
higher expression of the DRD2 long variant (thought to mediate postsynaptic actions),
as well as higher levels of DRD1 in the DLPFC (Kaalund et al. 2014); these results suggest that altered splicing may play a role in the pathophysiology of affective disorders.
Together, most of the evidence for dopaminergic dysfunction in the brains of subjects
with mood disorders comes from measuring dopamine synthesis, metabolism, and
transport, with less consistent findings for dopamine receptors. The findings suggest
that dopaminergic activity is diminished in subjects with mood disorders, and that
this deficit occurs through alterations in a variety of receptor variants as well as alterations in neurotransmitter release. Since dopamine is linked to motivation, concentration, and ability to experience pleasure, alterations in dopaminergic activity might
underlie deficits in these functions in individuals with mood disorders.
-
-
1
-
Evidence for Altered Brain-Derived Neurotrophic
Factor Function in Mood Disorders
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates neuron
survival, plasticity, and synaptic function (Barde 1989; Korte et al. 1995; Linnarsson et
al. 1997; Liu et al. 2004; Ma et al. 1998; Patterson et al. 1996). Given the importance of
185 Molecular and Cellular Neurobiology
https://t.me/med1917
BDNF to these basic brain functions, it is not surprising that BDNF dysfunction has
been linked to psychiatric disorders. Indeed, researchers have found evidence of low
levels of BDNF protein in the hippocampus (Banerjee et al. 2013; Dwivedi et al. 2003;
Karege et al. 2005) and the PFC (Dwivedi et al. 2003; Karege et al. 2005) of subjects who
died from suicide, and in the basolateral amygdala of female subjects with MDD (Guil
loux et al. 2012). Similarly, pro-BDNF is lower in the right hippocampus (Dunham et
al. 2009) and BDNF is lower in the anterior cingulate in subjects with MDD (Youssef et
al. 2018). Gene expression analyses are consistent with protein-level deficits associated
with mood disorders. For instance, evidence indicates lower levels of BDNF signaling
in the anterior cingulate and entorhinal cortex in subjects with MDD (Thompson Ray
et al. 2011; Tripp et al. 2012) and in the basolateral amygdala of female subjects with
MDD (Guilloux et al. 2012). Thus, multiple lines of evidence suggest that BDNF signal
ing is lower in the brains of subjects with mood disorders. Low levels of neurotrophic
support might underlie the reduced cell numbers reported in subjects with mood dis
orders (see section “Alterations in Cell Number and Morphology in Mood Disorders”
earlier in this chapter). Because so many factors (e.g., genetics, age, sex, stress) influence
BDNF, a number of different pathological pathways might lead to diminished BDNF
signaling and subsequent mood-related deficits. Understanding how BDNF interacts
with these factors might provide insight into why particular individuals are more sus
ceptible to developing mood disorders.
-
-
-
-
Conclusion
In summary, human postmortem brain studies suggest that subjects with mood disorders exhibit many differences compared to unaffected comparison subjects. Although
this chapter does not discuss all differences found in the postmortem brains of subjects
with mood disorders, we have summarized findings from four general themes. In
terms of number and morphology of brain cells, subjects with mood disorders appear
to have alterations in neurons, glia, dendritic spines, and dendritic complexity; many
of these findings are brain region specific. Subjects with mood disorders also exhibit
alterations related to glutamate and GABA, potentially with increased glutamate sig
naling and decreased GABA signaling. Evidence also suggests monoaminergic signaling dysfunction in the postmortem brains of subjects with mood disorders. Finally,
BDNF signaling appears to be lower in subjects with mood disorders.
These alterations might define different subtypes of mood disorder subjects (i.e.,
dysfunction in only one theme might be present in a particular mood disorder subtype).
For instance, subjects who died from suicide might represent a subtype exhibiting distinct human postmortem brain pathology. However, a substantial proportion of subjects who die from suicide also have a mood disorder, presenting a challenge to
disentangling the two. Studies that include subjects who died from suicide without a
mood disorder may provide important insight into suicide-specific brain alterations.
Indeed, evidence suggests that this may be the case, at least in terms of lower brain stem
levels of 5-HT or 5-HIAA in subjects who died from suicide, independent of psychiatric
diagnosis (Mann et al. 1989). Additionally, some postmortem brain differences seem
to distinguish MDD and bipolar disorder. For instance, subjects with MDD, but not
-
186 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
those with bipolar disorder, appear to exhibit smaller neuronal size in layer VI of the
subgenual anterior cingulate (Cotter et al. 2001) and lower oligodendrocyte density
in the basolateral amygdala (Hamidi et al. 2004). Also, subjects with bipolar disorder
seem to have lower DLPFC levels of both somatostatin and parvalbumin mRNA,
whereas subjects with MDD have a lower level of somatostatin mRNA, but not of
parvalbumin mRNA, in this cortical region (Sibille et al. 2009); these differences might
represent disease specificity in GABA-related alterations.
Another possibility to consider is that psychiatric medications may impact dependent measures investigated in the human postmortem brain. Although it is challenging to tease apart psychiatric medication effects, given that most subjects with mood
disorders included in postmortem brain studies were taking at least one of these med
ications at the time of death, some studies have examined antidepressant-free subjects
and still found differences from unaffected comparison subjects. For instance, lower
striatal levels of dihydroxyphenylacetic acid were reported in antidepressant-free subjects with MDD who died from suicide, and higher PFC binding levels were reported
for β
-adrenoreceptors in antidepressant-free subjects with MDD (Rivero et al. 2014).
1
Although we have considered each of the four themes separately, it is likely that
these alterations co-occur and interact in the brains of subjects with mood disorders.
At this time, it is not possible to conclude whether these alterations co-occur, because
most previous studies investigated measures relevant to only one theme. If alterations
related to these four themes do co-occur in the brains of subjects with mood disorders,
it is possible that one “upstream” factor (e.g., stress exposure, with potential interac
tion with genetic susceptibility) drives brain alterations related to all described
themes. Indeed, evidence from rodent studies suggests that this may be the case, at
least with respect to stress exposure. For instance, chronic stress leads to structural
changes in brain cells, glutamate- and GABA-related alterations, monoaminergic dysfunction, and lower brain BDNF levels (reviewed in Belleau et al. 2019; Nowacka and
Obuchowicz 2013). Researchers have yet to determine whether chronic stress, either
during early life or in adulthood, might interact with genes, resulting in the postmortem brain pathology fitting all described themes.
In general, future postmortem studies should carefully consider cohort design,
with adequate statistical power, as a strategy for disentangling the effects of disease,
suicide, and/or psychiatric medications on brain alterations in mood disorders. Future studies might also examine multiple dependent measures (e.g., systems affected
by stress exposures) that cross-cut these general themes.
-
-
References
Arango V, Ernsberger P, Sved AF, et al: Quantitative autoradiography of alpha 1- and alpha 2-
adrenergic receptors in the cerebral cortex of controls and suicide victims. Brain Res 630(1–
2):271–282, 1993 8118693
Banerjee R, Ghosh AK, Ghosh B, et al: Decreased mRNA and protein expression of BDNF, NGF,
and their receptors in the hippocampus from suicide: an analysis in human postmortem
brain. Clin Med Insights Pathol 6:1–11, 2013 24031163
Barde YA: Trophic factors and neuronal survival. Neuron 2(6):1525–1534, 1989 2697237
187 Molecular and Cellular Neurobiology
https://t.me/med1917
Belleau EL, Treadway MT, Pizzagalli DA: The impact of stress and major depressive disorder
on hippocampal and medial prefrontal cortex morphology. Biol Psychiatry 85(6):443–453,
2019 30470559
Beskow J, Gottfries CG, Roos BE, et al: Determination of monoamine and monoamine metabo-
lites in the human brain: post mortem studies in a group of suicides and in a control group.
Acta Psychiatr Scand 53(1):7–20, 1976 1251756
Boldrini M, Santiago AN, Hen R, et al: Hippocampal granule neuron number and dentate
gyrus volume in antidepressant-treated and untreated major depression. Neuropsycho
pharmacology 38(6):1068–1077, 2013 23303074
Boldrini M, Galfalvy H, Dwork AJ, et al: Resilience is associated with larger dentate gyrus,
while suicide decedents with major depressive disorder have fewer granule neurons. Biol
Psychiatry 85(10):850–862, 2019 30819514
Bowley MP, Drevets WC, Ongür D, et al: Low glial numbers in the amygdala in major depres-
sive disorder. Biol Psychiatry 52(5):404–412, 2002 12242056
Cobb JA, O’Neill K, Milner J, et al: Density of GFAP-immunoreactive astrocytes is decreased in
left hippocampi in major depressive disorder. Neuroscience 316:209–220, 2016 26742791
Cotter D, Mackay D, Landau S, et al: Reduced glial cell density and neuronal size in the anterior
cingulate cortex in major depressive disorder. Arch Gen Psychiatry 58(6):545–553, 2001
11386983
Cottingham C, Wang Q: Alpha2 adrenergic receptor dysregulation in depressive disorders: im-
plications for the neurobiology of depression and antidepressant therapy. Neurosci Biobehav Rev 36(10):2214–2225, 2012 22910678
DeFelipe J, Fariñas I: The pyramidal neuron of the cerebral cortex: morphological and chemical
characteristics of the synaptic inputs. Prog Neurobiol 39(6):563–607, 1992 1410442
DeFelipe J, López-Cruz PL, Benavides-Piccione R, et al: New insights into the classification and
nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci 14(3):202–216, 2013
23385869
Douglas RJ, Martin KA: Mapping the matrix: the ways of neocortex. Neuron 56(2):226–238, 2007
17964242
Douillard-Guilloux G, Lewis D, Seney ML, et al: Decrease in somatostatin-positive cell density
in the amygdala of females with major depression. Depress Anxiety 34(1):68–78, 2017
27557481
Dunham JS, Deakin JF, Miyajima F, et al: Expression of hippocampal brain-derived neuro-
trophic factor and its receptors in Stanley consortium brains. J Psychiatr Res 43(14):1175–
1184, 2009 19376528
Dunlop BW, Nemeroff CB: The role of dopamine in the pathophysiology of depression. Arch
Gen Psychiatry 64(3):327–337, 2007 17339521
Dwivedi Y, Rizavi HS, Conley RR, et al: Altered gene expression of brain-derived neurotrophic
factor and receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch Gen
Psychiatry 60(8):804–815, 2003 12912764
Ferrier IN, McKeith IG, Cross AJ, et al: Postmortem neurochemical studies in depression. Ann
NY Acad Sci 487:128–142, 1986 2436529
Fino E, Packer AM, Yuste R: The logic of inhibitory connectivity in the neocortex. Neuroscien-
tist 19(3):228–237, 2013 22922685
Fitzgerald ML, Kassir SA, Underwood MD, et al: Dysregulation of striatal dopamine receptor
binding in suicide. Neuropsychopharmacology 42(4):974–982, 2017 27402414
Glantz LA, Lewis DA: Decreased dendritic spine density on prefrontal cortical pyramidal neu-
rons in schizophrenia. Arch Gen Psychiatry 57(1):65–73, 2000 10632234
Gray AL, Hyde TM, Deep-Soboslay A, et al: Sex differences in glutamate receptor gene expres-
sion in major depression and suicide. Mol Psychiatry 20(9):1057–1068, 2015 26169973
Gross-Isseroff R, Weizman A, Fieldust SJ, et al: Unaltered alpha(2)-noradrenergic/imidazoline
receptors in suicide victims: a postmortem brain autoradiographic analysis. Eur Neuropsychopharmacol 10(4):265–271, 2000 10871708
-
188 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
Guilloux JP, Douillard-Guilloux G, Kota R, et al: Molecular evidence for BDNF- and GABA-
related dysfunctions in the amygdala of female subjects with major depression. Mol Psy
chiatry 17(11):1130–1142, 2012 21912391
Hamidi M, Drevets WC, Price JL: Glial reduction in amygdala in major depressive disorder is
due to oligodendrocytes. Biol Psychiatry 55(6):563–569, 2004 15013824
Hashimoto K, Sawa A, Iyo M: Increased levels of glutamate in brains from patients with mood
disorders. Biol Psychiatry 62(11):1310–1316, 2007 17574216
Hercher C, Canetti L, Turecki G, et al: Anterior cingulate pyramidal neurons display altered
dendritic branching in depressed suicides. J Psychiatr Res 44(5):286–293, 2010 19765721
Honig A, Bartlett JR, Bouras N, et al: Amino acid levels in depression: a preliminary investiga-
tion. J Psychiatr Res 22(3):159–164, 1988 3225786
Kaalund SS, Newburn EN, Ye T, et al: Contrasting changes in DRD1 and DRD2 splice variant
expression in schizophrenia and affective disorders, and associations with SNPs in post
mortem brain. Mol Psychiatry 19(12):1258–1266, 2014 24322206
Kang HJ, Voleti B, Hajszan T, et al: Decreased expression of synapse-related genes and loss of
synapses in major depressive disorder. Nat Med 18(9):1413–1417, 2012 22885997
Karege F, Vaudan G, Schwald M, et al: Neurotrophin levels in postmortem brains of suicide vic-
tims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain
Res 136(1–2):29–37, 2005 15893584
Karolewicz B, Maciag D, O’Dwyer G, et al: Reduced level of glutamic acid decarboxylase-67
kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 13(4):411–
420, 2010 20236554
Klempan TA, Sequeira A, Canetti L, et al: Altered expression of genes involved in ATP biosyn-
thesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with
and without major depression. Mol Psychiatry 14(2):175–189, 2009 17938633
Klimek V, Stockmeier C, Overholser J, et al: Reduced levels of norepinephrine transporters in
the locus coeruleus in major depression. J Neurosci 17(21):8451–8458, 1997 9334417
Klimek V, Schenck JE, Han H, et al: Dopaminergic abnormalities in amygdaloid nuclei in major
depression: a postmortem study. Biol Psychiatry 52(7):740–748, 2002 12372665
Konopaske GT, Lange N, Coyle JT, et al: Prefrontal cortical dendritic spine pathology in schizo-
phrenia and bipolar disorder. JAMA Psychiatry 71(12):1323–1331, 2014 25271938
Korte M, Carroll P, Wolf E, et al: Hippocampal long-term potentiation is impaired in mice lack-
ing brain-derived neurotrophic factor. Proc Natl Acad Sci USA 92(19):8856–8860, 1995
7568031
Lan MJ, McLoughlin GA, Griffin JL, et al: Metabonomic analysis identifies molecular changes
associated with the pathophysiology and drug treatment of bipolar disorder. Mol Psychiatry 14(3):269–279, 2009 18256615
Linnarsson S, Björklund A, Ernfors P: Learning deficit in BDNF mutant mice. Eur J Neurosci
9(12):2581–2587, 1997 9517463
Liu IY, Lyons WE, Mamounas LA, et al: Brain-derived neurotrophic factor plays a critical role
in contextual fear conditioning. J Neurosci 24(36):7958–7963, 2004 15356210
Ma YT, Hsieh T, Forbes ME, et al: BDNF injected into the superior colliculus reduces develop-
mental retinal ganglion cell death. J Neurosci 18(6):2097–2107, 1998 9482796
Maciag D, Hughes J, O’Dwyer G, et al: Reduced density of calbindin immunoreactive GABA-
ergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biol Psychiatry 67(5):465–470, 2010 20004363
Mann JJ, Arango V, Marzuk PM, et al: Evidence for the 5-HT hypothesis of suicide. A review
of post-mortem studies. Br J Psychiatry 155 (suppl 8):7–14, 1989 2692642
Miguel-Hidalgo JJ, Waltzer R, Whittom AA, et al: Glial and glutamatergic markers in depres-
sion, alcoholism, and their comorbidity. J Affect Disord 127(1–3):230–240, 2010 20580095
Moses SG, Robins E: Regional distribution of norepinephrine and dopamine in brains of de-
pressive suicides and alcoholic suicides. Psychopharmacol Commun 1(3):327–337, 1975
1224002
-
-
189 Molecular and Cellular Neurobiology
https://t.me/med1917
Nowacka M, Obuchowicz E: BDNF and VEGF in the pathogenesis of stress-induced affective
diseases: an insight from experimental studies. Pharmacol Rep 65(3):535–546, 2013
23950576
Ongür D, Drevets WC, Price JL: Glial reduction in the subgenual prefrontal cortex in mood dis-
orders. Proc Natl Acad Sci USA 95(22):13290–13295, 1998 9789081
Orrego F, Villanueva S: The chemical nature of the main central excitatory transmitter: a critical
appraisal based upon release studies and synaptic vesicle localization. Neuroscience
56(3):539–555, 1993 7902967
Packer AM, McConnell DJ, Fino E, et al: Axo-dendritic overlap and laminar projection can
explain interneuron connectivity to pyramidal cells. Cereb Cortex 23(12):2790–2802, 2013
22941716
Pare CM, Yeung DP, Price K, et al: 5-Hydroxytryptamine, noradrenaline, and dopamine in
brainstem, hypothalamus, and caudate nucleus of controls and of patients committing sui
cide by coal-gas poisoning. Lancet 2(7612):133–135, 1969 4183246
Patterson SL, Abel T, Deuel TA, et al: Recombinant BDNF rescues deficits in basal synaptic
transmission and hippocampal LTP in BDNF knockout mice. Neuron 16(6):1137–1145, 1996
8663990
Pizzagalli DA, Berretta S, Wooten D, et al: Assessment of striatal dopamine transporter binding
in individuals with major depressive disorder: in vivo positron emission tomography and
postmortem evidence. JAMA Psychiatry 76(8):854–861, 2019 31042280
Rajkowska G, Miguel-Hidalgo JJ, Wei J, et al: Morphometric evidence for neuronal and glial pre-
frontal cell pathology in major depression. Biol Psychiatry 45(9):1085–1098, 1999 10331101
Rajkowska G, O’Dwyer G, Teleki Z, et al: GABAergic neurons immunoreactive for calcium
binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 32(2):471–482, 2007 17063153
Riederer P, Birkmayer W, Seemann D, et al: 4-Hydroxy-3-methoxyphenylglycol as an index of
brain noradrenaline turnover in endogenous depression. Acta Psychiatr Scand Suppl
280:251–257, 1980 6996431
Rivero G, Gabilondo AM, García-Sevilla JA, et al: Increased alpha2- and beta1-adrenoceptor
densities in postmortem brain of subjects with depression: differential effect of antidepressant treatment. J Affect Disord 167:343–350, 2014 25020269
Rubinow MJ, Mahajan G, May W, et al: Basolateral amygdala volume and cell numbers in ma-
jor depressive disorder: a postmortem stereological study. Brain Struct Funct 221(1):171–
184, 2016 25287512
Seney ML, Tripp A, McCune S, et al: Laminar and cellular analyses of reduced somatostatin
gene expression in the subgenual anterior cingulate cortex in major depression. Neurobiol
Dis 73:213–219, 2015 25315685
Sequeira A, Klempan T, Canetti L, et al: Patterns of gene expression in the limbic system of sui-
cides with and without major depression. Mol Psychiatry 12(7):640–655, 2007 17353912
Sequeira A, Mamdani F, Ernst C, et al: Global brain gene expression analysis links glutamater-
gic and GABAergic alterations to suicide and major depression. PLoS One 4(8):e6585, 2009
19668376
Sibille E, Wang Y, Joeyen-Waldorf J, et al: A molecular signature of depression in the amygdala.
Am J Psychiatry 166(9):1011–1024, 2009 19605536
Soetanto A, Wilson RS, Talbot K, et al: Association of anxiety and depression with microtubule-
associated protein 2- and synaptopodin-immunolabeled dendrite and spine densities in
hippocampal CA3 of older humans. Arch Gen Psychiatry 67(5):448–457, 2010 20439826
Stockmeier CA: Involvement of serotonin in depression: evidence from postmortem and imag-
ing studies of serotonin receptors and the serotonin transporter. J Psychiatr Res 37(5):357–
373, 2003 12849929
Stockmeier CA, Mahajan GJ, Konick LC, et al: Cellular changes in the postmortem hippocam-
pus in major depression. Biol Psychiatry 56(9):640–650, 2004 15522247
Thompson Ray M, Weickert CS, Wyatt E, et al: Decreased BDNF, trkB-TK+ and GAD67 mRNA
expression in the hippocampus of individuals with sc
J Psychiatry Neurosci 36(3):195–203, 2011 21223646
hizophrenia and mood disorders.
-
190 The APA Publishing Textbook of Mood Disorders, Second Edition
https://t.me/med1917
Tripp A, Oh H, Guilloux JP, et al: Brain-derived neurotrophic factor signaling and subgenual
anterior cingulate cortex dysfunction in major depressive disorder. Am J Psychiatry
169(11):1194–1202, 2012 23128924
Wamsley B, Fishell G: Genetic and activity-dependent mechanisms underlying interneuron di-
versity. Nat Rev Neurosci 18(5):299–309, 2017 28381833
Xiang L, Szebeni K, Szebeni A, et al: Dopamine receptor gene expression in human amygdaloid
nuclei: elevated D4 receptor mRNA in major depression. Brain Res 1207:214–224, 2008
18371940
Youssef MM, Underwood MD, Huang YY, et al: Association of BDNF Val66Met polymorphism
and brain BDNF levels with major depression and suicide. Int J Neuropsychopharmacol
21(6):528–538, 2018 29432620
Zhu MY, Klimek V, Dilley GE, et al: Elevated levels of tyrosine hydroxylase in the locus coeru-
leus in major depression. Biol Psychiatry 46(9):1275–1286, 1999 10560033
CHAPTER 11
https://t.me/med1917
Brain Imaging
Michele A. Bertocci, Ph.D.
Jorge Renner Cardoso de Almeida, M.D., Ph.D.
Stephen M. Strakowski, M.D.
Mary L. Phillips, M.D., M.D. (Cantab)
Mood (affective) disorders are among the leading causes of disability
worldwide. Surveys suggest that depression is the leading cause of disability in highincome countries. Up to 30% of people with mood disorders suffer from chronic, often
lifelong illness. Mood disorders include episodes of depressed mood (depression)
and elevated mood (mania), both separately and in combination, and are believed to
arise from dysregulation in neural network structure and function that can be measured in vivo using brain imaging techniques. These techniques include magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission
computed tomography (SPECT), computed axial tomography (CT), optical imaging,
cranial ultrasound, and magnetoencephalography (MEG), through which measures
of structure, function, energy metabolism, and neurotransmitter concentrations can
be acquired. In this chapter, we focus on neural abnormalities measured with MRI,
PET, and SPECT, because these techniques have the most robust datasets at this time.
To start, we provide a brief review of how these techniques image the brain. MRI
takes advantage of the magnetism of atoms—usually hydrogen (a single proton)—in
water, tissue, myelin, and other molecules to measure structure, function, and concentrations of neurochemicals. MRI can differentiate gray and white matter and cerebrospinal fluid in the brain, allowing measurement of neural structures that may be
important in mood disorder pathology. Gray matter consists mostly of neuronal cell
bodies and can be measured by volume and thickness. White matter consists mostly
of myelinated axons; measurements of white matter generally reflect the movement
of water along the axon and include volume, length, radial diffusivity, longitudinal
diffusivity, and fractional anisotropy, as well as newer measures using spectral diffusion. Using the same magnetic characteristic of hydrogen atoms, MRI can be used to
acquire proxy measures of neural activity using two approaches, blood oxygen level–
191
Соседние файлы в папке Библиотека им академика М.И. Перельмана