The n e w e ng l a n d j o u r na l of m e dic i n e
clinical implications of basic research
Molecules That Mediate Mood
Michael E. Thase, M.D.
Major depressive disorder is now recognized as
one of the world’s greatest public health prob-
lems: it is common, typically follows a relapsing
or recurrent course, disrupts the performance of
social and vocational roles, and is associated with
increased medical morbidity and reduced life ex-
pectancy.1 During the past several decades, anti-
depressant medications have become the most
widely used means to lessen the suffering and
impairments associated with this heterogeneous
illness.
Newer medications — such as selective sero-
tonin-reuptake inhibitors and serotonin- and nor-
epinephrine-reuptake inhibitors — have improved
on the older standard, the tricyclic antidepres-
sants, in terms of side-effect profiles, ease of use,
and lower lethality in case of overdose. However,
these newer first-line and second-line therapies
still have clear limitations, and less than 50% of
patients who begin therapy will be well 1 year
later, even under relatively favorable treatment
conditions.2
Identification of new antidepressant medica-
tions that either broaden the range of effective-
ness or have even better tolerability profiles thus
continues to be an important area for research.
Since the field may be approaching a point of di-
minishing returns with respect to new drugs that
block serotonin and norepinephrine transporters,
attention is shifting to other mechanisms that
may mediate changes in relevant neuronal and ge-
nomic events implicated in the response to anti-
depressants.
The a recent study by Berton and colleagues3
is therefore relevant to neuroscientists, clinicians,
and depressed people and their loved ones. To
briefly summarize, the investigators have been
studying the molecular correlates of learned help-
lessness, one of the best-validated animal models
of human depression. Learned helplessness is a
behavioral deficit state that is experimentally in-
duced by placing the laboratory animal in a sit-
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uation in which it is impossible to escape aver-
sive stimulation; over time the animals learn to
“cut their losses” by adopting a passive behav-
ioral repertoire, which characteristically persists
for some time after the situation changes and
escape is possible. There are differences that are
specific to both the species and the strain in the
development of learned helplessness, as well as
individual differences within species and strains.
Some animals are more resistant (they continue
to try escaping) or resilient (they either continue
to try to escape or remain helpless for a shorter
time after escape is possible).
Previous research had shown that learned help-
lessness is reliably associated with the induction
of transcription factor ΔFosB in several relevant
regions of the brain, including the dorsal raphe
nucleus (the brain’s principal source of seroto-
nin), the locus ceruleus (the brain’s principal
source of norepinephrine), and the ventrolateral
periaqueductal gray substance, a region essential
for the perception of pain and a site rich in neu-
rons containing the neuropeptide neurotransmit-
ter substance P, the endogenous agonist for neu-
rokinin-1 receptors.
Berton et al. have now found that levels of
ΔFosB are highly predictive of individual differ-
ences in the magnitude of behavioral effect of in-
escapable shock. Specifically, animals with the
strongest ΔFosB responses in the ventrolateral
periaqueductal gray substance were the most re-
sistant or resilient to the behavioral consequences
of learned helplessness. This association was so
strong (r = 0.69) that one might surmise that half
of the variance in behavioral outcomes could be
explained by induction of ΔFosB expression.
The investigators further found that induction
of ΔFosB predominates in neurons with positive
staining for substance P and that the gene en-
coding substance P is down-regulated by ΔFosB
(Fig. 1). To test whether ΔFosB-modulated expres-
sion of substance P in neurons in the ventrolat-
 Clinical Implications of Basic Research

Injection of viral vector containing Injection of viral vector containing

gene encoding ∆FosB gene encoding β-galactosidase
(control)

∆FosB LacZ

Inescapable stress

Brain of mouse

Ventrolateral
periaqueductal gray

Nucleus
accumbens

∆FosB Substance
protein Transcription of P protein
substance P gene
X
NK1
receptor
Substance
P gene

∆FosB binds promotor of

substance P gene and blocks
transcription
Binding of substance P by
NK1 receptor potentiates
GABAergic neurons

Resistance and resilience to Learned helplessness

learned helplessness

Figure 1. Induction of Overexpression of Transcription Factor ΔFosB.

The injection of a viral vector into a mouse alters the animal’s neurochemical and behavioral responses to inescap-
able stress. Then inhibition of substance P synthesis by ΔFosB in the ventrolateral periaqueductal gray region re-
sults in reduced inhibition of escape behaviors mediated by γ-aminobutyric acid (GABA) in the nucleus accumbens.
NK1 denotes neurokinin 1.

eral periaqueductal gray substance influences
substance P–mediated neurotransmission in the
forebrain, the investigators engineered mice to
overexpress ΔFosB or an inactive plasmid con-
taining a β-galactosidase and a LacZ construct
(as a control) and measured the release of sub-
stance P in the nucleus accumbens, both under
baseline conditions and after exposure to stress.
The nucleus accumbens, which joins with the
olfactory tubercle to make up the ventral stria-
tum, plays an important role in appetitive and
other reward behaviors and thus is directly im-
plicated in mediating some of the behavioral def-
icits of depression in humans. Although the over-
expression of ΔFosB did not significantly change
baseline extracellular concentrations of substance
COLOR FIGURE

Version 3 11/16/07
Author Thase 2401
n engl j med 357;23  www.nejm.org  december 6, 2007 Fig # 1
Title Learned helplessness
The New England Journal of Medicine ME MP
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BP
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AUTHOR PLEASE NOTE:
 Clinical Implications of Basic Research

P in the nucleus accumbens, it did significantly
suppress an increase in substance P levels in re-
sponse to two standardized laboratory stressors
(foot shocks and the forced-swim test). The inves-
tigators observed similar effects by administering
a tricyclic antidepressant, desipramine, in order
to gauge the relative effect of an established an-
tidepressant drug that has been shown to reverse
learned helplessness, and a specific antagonist of
the neurokinin-1 receptor, which blocks the down-
stream effects of substance P (in this case, block-
ing the potentiation of neurons inhibited by
γ-aminobutyric acid in the nucleus accumbens,
which may mediate at least some of the behavioral
deficits of the learned-helplessness state).
There is no doubt that better antidepressants
working through mechanisms other than the in-
gion of greatest interest in the ventrolateral peri-
aqueductal gray substance, and underscore the
relevance of substance P as a target for pharma-
cologic intervention. The finding that overexpres-
sion of ΔFosB changes behavioral phenotype
(from stress-sensitive to stress-resilient) may well
provide a glimpse of future psychopharmacologic
strategies, particularly if such manipulations have
durable phenotypic effects. The fact that clinical
studies have not yet confirmed a consistent anti-
depressant effect for specific neurokinin-1–recep-
tor antagonists may further reinforce efforts to
look at treatments that more directly target in-
tracellular mechanisms, such as the activity of
ΔFosB.
No potential conflict of interest relevant to this article was re-
ported.

hibition of serotonin and norepinephrine trans-
porters would be of value to the medical commu-
nity. A large leap of faith and much work are
needed to bridge these experiments and the intro-
duction of a safe treatment for people with the
complex, heterogeneous condition of depression.
Nevertheless, the findings of Berton et al. advance
the field with respect to clarifying the neural ba-
sis of individual differences in behavioral respons-
es to sustained inescapable stress. In this regard,
their experiments identify ΔFosB as an important
mediator of behavioral responses, localize the re-
From the University of Pennsylvania School of Medicine and
the Veterans Affairs Medical Center — both in Philadelphia;
and the University of Pittsburgh Medical Center, Pittsburgh.
1. Kessler RC, Merikangas KR, Wang PS. Prevalence, comor-
bidity, and service utilization for mood disorders in the United
States at the beginning of the twenty-first century. Annu Rev
Clin Psychol 2007;3:137-58.
2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-
term outcomes in depressed outpatients requiring one or several
treatment steps: a STAR*D report. Am J Psychiatry 2006;163:1905-
17.
3. Berton O, Covington HE III, Ebner K, et al. Induction of
deltaFosB in the periaqueductal gray by stress promotes active
coping responses. Neuron 2007;55:289-300.
Copyright © 2007 Massachusetts Medical Society.

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