Anhedonia Following Early-Life Adversity Involves Aberrant Interaction of Reward and Anxiety Circuits and Is Reversed by Partial Silencing of Amygdala Corticotropin-Releasing Hormone Gene

doi:10.1016/j.biopsych.2017.08.023

Biological Psychiatry

Volume 83, Issue 2, 15 January 2018, Pages 137-147

https://doi.org/10.1016/j.biopsych.2017.08.023 Get rights and content

Abstract

Background

Anhedonia, the diminished ability to experience pleasure, is an important dimensional entity linked to depression, schizophrenia, and other emotional disorders, but its origins and mechanisms are poorly understood. We have previously identified anhedonia, manifest as decreased sucrose preference and social play, in adolescent male rats that experienced chronic early-life adversity/stress (CES). Here we probed the molecular, cellular, and circuit processes underlying CES-induced anhedonia and tested them mechanistically.

Methods

We examined functional brain circuits and neuronal populations activated by social play in adolescent CES and control rats. Structural connectivity between stress- and reward-related networks was probed using high-resolution diffusion tensor imaging, and cellular/regional activation was probed using c-Fos. We employed viral-genetic approaches to reduce corticotropin-releasing hormone (Crh) expression in the central nucleus of the amygdala in anhedonic rats, and tested for anhedonia reversal in the same animals.

Results

Sucrose preference was reduced in adolescent CES rats. Social play, generally considered an independent measure of pleasure, activated brain regions involved in reward circuitry in both control and CES groups. In CES rats, social play activated Crh-expressing neurons in the central nucleus of the amygdala, typically involved in anxiety/fear, indicating aberrant functional connectivity of pleasure/reward and fear circuits. Diffusion tensor imaging tractography revealed increased structural connectivity of the amygdala to the medial prefrontal cortex in CES rats. Crh-short hairpin RNA, but not control short hairpin RNA, given into the central nucleus of the amygdala reversed CES-induced anhedonia without influencing other emotional measures.

Conclusions

These findings robustly demonstrate aberrant interactions of stress and reward networks after early-life adversity and suggest mechanistic roles for Crh-expressing amygdala neurons in emotional deficits portending major neuropsychiatric disorders.

Section snippets

Animals

Primiparous, time-pregnant Sprague Dawley rat dams were obtained from Harlan (now Envigo, Livermore, CA) on embryonic day 15, and maintained in an uncrowded, quiet animal facility room on a 12-hour light/dark cycle with ad libitum access to lab chow and water. Parturition was checked daily, and the day of birth was considered postnatal day 0. Four separate cohorts of rats were used, as described below. All experiments were performed in accordance with National Institutes of Health guidelines

Preference for Sucrose Is Diminished in Adolescent Male Rats That Experienced Early-Life Adversity

Sucrose consumption was significantly lower in 56-day-old rats that had experienced early-life stress (F_1,21 = 8.85, p < .01) (Figure 1B, C), in line with our prior report (15). This was the case for both absolute sucrose consumption as well as the proportion (%) of the dilute sucrose solution of overall fluid intake (Supplemental Figure S2A, B). Reduced sucrose preference is generally considered an indicator of anhedonia.

Aberrant Structural Connectivity of Stress and Pleasure/Reward Circuits in CES Rats

Complex behaviors including pleasure/reward and fear/anxiety are mediated

Discussion

Here we demonstrate that early-life adversity provokes severe anhedonia by altering interactions of pleasure/reward and stress-related networks involving CRF-producing neurons in the amygdala. Specifically, we found that CES caused anhedonia, measured as decreased sucrose preference and reduced social play. During the normally pleasurable experience of play, early-life stress resulted in augmented, abnormal activation of CRF-producing neurons in the ACe of adolescent rats compared with control

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. RO1s MH73136, NS28912, and P50 MH096889 (to TZB), and a George E. Hewitt Foundation for Medical Research postdoctoral fellowship (to JLB).

We thank Gissell A. Sanchez, Jennifer Daglian, and Pamela A. See for technical assistance.

The authors report no biomedical financial interests or potential conflicts of interest.

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Anhedonia, an impairment in the motivation for or experience of pleasure, is a well-established transdiagnostic harbinger and core symptom of mental illness. Given increasing recognition of early life origins of mental illness, we posit that anhedonia should, and could, be recognized earlier if appropriate tools were available. However, reliable diagnostic instruments prior to childhood do not currently exist.
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Patterns of sensory inputs early in life play an integral role in shaping the maturation of neural circuits, including those implicated in emotion and cognition. In both experimental animal models and observational human research, unpredictable sensory signals have been linked to aberrant developmental outcomes, including poor memory and effortful control. These findings suggest that sensitivity to unpredictable sensory signals is conserved across species and sculpts the developing brain. The current study provides a novel investigation of unpredictable maternal sensory signals in early life and child internalizing behaviors. We tested these associations in three independent cohorts to probe the generalizability of associations across continents and cultures.
The three prospective longitudinal cohorts were based in Orange, USA (n = 163, 47.2 % female, M_age = 1 year); Turku, Finland (n = 239, 44.8 % female, M_age = 5 years); and Irvine, USA (n = 129, 43.4 % female, M_age = 9.6 years). Unpredictability of maternal sensory signals was quantified during free-play interactions. Child internalizing behaviors were measured via parent report (Orange & Turku) and child self-report (Irvine).
Early life exposure to unpredictable maternal sensory signals was associated with greater child fearfulness/anxiety in all three cohorts, above and beyond maternal sensitivity and sociodemographic factors. The association between unpredictable maternal sensory signals and child sadness/depression was relatively weaker and did not reach traditional thresholds for statistical significance.
The correlational design limits our ability to make causal inferences.
Findings across the three diverse cohorts suggest that unpredictable maternal signals early in life shape the development of internalizing behaviors, particularly fearfulness and anxiety.
Early life adversity reduces affiliative behavior with a stressed cagemate and leads to sex-specific alterations in corticosterone responses in adult mice
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Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both groups of mice 20 or 90 min after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.
Anhedonia and Delay Discounting: Differing Patterns of Brain-Behavior Relationships in Healthy Control Participants Versus Individuals With Posttraumatic Stress Disorder
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Anhedonia may contribute to individual differences in delay discounting (DD). In prior work, we found that higher anhedonia was associated with shallower DD in healthy control (HC) participants but steeper DD in individuals with posttraumatic stress disorder (PTSD). In this study, we aimed to directly compare the relationship between anhedonia and DD across groups and to identify functional brain correlates of this interaction.
Participants (HC group: n = 23, DSM-5 PTSD group: n = 23) completed a questionnaire assessing anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS]), task-based functional magnetic resonance imaging of decision making including DD, and resting-state functional magnetic resonance imaging. Task-based activity and resting-state functional connectivity were evaluated in reward-related regions that have also been implicated in PTSD (nucleus accumbens [NAcc], right anterior insula).
Higher SHAPS scores were associated with steeper DD in PTSD, but there was no relationship between DD and SHAPS in the HC group. There was a significant group-by-SHAPS interaction for NAcc activity, t₃₁ = 2.92, p = .007: Greater NAcc activity when immediate rewards were chosen was associated with higher SHAPS in the PTSD group but lower SHAPS in the HC group. In resting-state functional connectivity, there was a group-by-SHAPS interaction between the NAcc seed and right parietal and frontal pole clusters.
These results extend prior findings that anhedonia is associated with steeper DD in PTSD and demonstrate that this behavioral finding occurs in the context of NAcc hyperactivity to immediate rewards and hyperconnectivity in anhedonic individuals with PTSD.
Postpartum scarcity-adversity inflicts sex-specific cerebellar adaptations and reward behaviors in adolescence
2023, Pharmacology Biochemistry and Behavior
Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.
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Early-life adversity (ELA) is associated with increased risk for mood disorders, including depression and substance use disorders. These disorders are characterized by impaired reward-related behaviors, suggesting compromised operations of reward-related brain circuits. However, the brain regions engaged by ELA that mediate these enduring consequences of ELA remain largely unknown. In an animal model of ELA, we identified aberrant reward-seeking behaviors, a discovery that provides a framework for assessing the underlying circuits.
Employing TRAP2 (targeted recombination in active populations) male and female mice, in which neurons activated within a defined time frame are permanently tagged, we compared ELA- and control-reared mice, assessing the quantity and distribution of ELA-related neuronal activation. After validating the TRAP2 results using native c-Fos labeling, we defined the molecular identity of this population of activated neurons.
We uniquely demonstrated that the TRAP2 system is feasible and efficacious in neonatal mice. Surprisingly, the paraventricular nucleus of the thalamus was robustly and almost exclusively activated by ELA and was the only region distinguishing ELA from typical rearing. Remarkably, a large proportion of ELA-activated paraventricular nucleus of the thalamus neurons expressed CRF₁, the receptor for the stress-related peptide, corticotropin-releasing hormone, but these neurons did not express corticotropin-releasing hormone itself.
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Archival ReportAnhedonia Following Early-Life Adversity Involves Aberrant Interaction of Reward and Anxiety Circuits and Is Reversed by Partial Silencing of Amygdala Corticotropin-Releasing Hormone Gene

Abstract

Background

Methods

Results

Conclusions

Section snippets

Animals

Preference for Sucrose Is Diminished in Adolescent Male Rats That Experienced Early-Life Adversity

Aberrant Structural Connectivity of Stress and Pleasure/Reward Circuits in CES Rats

Discussion

Acknowledgments and Disclosures

The link between childhood trauma and depression: Insights from HPA axis studies in humans

Psychoneuroendocrinology

Epigenetics of stress-related psychiatric disorders and gene × environment interactions

Neuron

Foundations of posttraumatic stress disorder: Does early life trauma lead to adult posttraumatic stress disorder?

Dev Psychopathol

Gene × environment determinants of stress- and anxiety-related disorders

Annu Rev Psychol

Early life adversity reduces stress reactivity and enhances impulsive behavior: Implications for health behaviors

Int J Psychophysiol

Enhancing glutamatergic transmission during adolescence reverses early-life stress-induced deficits in the rewarding effects of cocaine in rats

Neuropharmacology

Effects of early-life abuse differ across development: Infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala

J Neurosci

Sex-specific and strain-dependent effects of early life adversity on behavioral and epigenetic outcomes

Front Psychiatry

New insights into early-life stress and behavioral outcomes

Curr Opin Behav Sci

Emergence of social behavior deficit, blunted corticolimbic activity and adult depression-like behavior in a rodent model of maternal maltreatment

Transl Psychiatry

Diagnostic and Statistical Manual of Mental Disorders, 5th ed

Reward processing dysfunction in major depression, bipolar disorder and schizophrenia

Curr Opin Psychiatry

Reconceptualizing anhedonia: Novel perspectives on balancing the pleasure networks in the human brain

Front Behav Neurosci

Fragmentation and high entropy of neonatal experience predict adolescent emotional outcome

Transl Psychiatry

The neurobiology of anhedonia and other reward-related deficits

Trends Neurosci

An animal model of anhedonia: Attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress

Psychopharmacology (Berl)

The pleasures of play: Pharmacological insights into social reward mechanisms

Trends Pharmacol Sci

Toward a functional neuroanatomy of pleasure and happiness

Trends Cogn Sci

The neuro-symphony of stress

Nat Rev Neurosci

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Nat Rev Neurosci

Role of the brain’s reward circuitry in depression: Transcriptional mechanisms

Int Rev Neurobiol

The brain reward circuitry in mood disorders

Nat Rev Neurosci

Neurobiology of resilience

Nat Neurosci

Toward understanding how early-life stress reprograms cognitive and emotional brain networks

Neuropsychopharmacology

Sex differences in prenatal epigenetic programming of stress pathways

Stress

Epigenetic signaling in psychiatric disorders: Stress and depression

Dialogues Clin Neurosci

From vulnerability to neurotoxicity: A developmental approach to the effects of stress on the brain and behavior

Epigenetic risk factors for diseases: A transgenerational perspective

Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse

Nat Neurosci

Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress

Science

Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress

Dev Neurosci

Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex

Neuropsychopharmacology

Stress, sensitive periods and maturational events in adolescent depression

Trends Neurosci

The brain on stress: Vulnerability and plasticity of the prefrontal cortex over the life course

Neuron

Hyper-excitability and epilepsy generated by chronic early-life stress

Neurobiol Stress

Region-specific onset of handling-induced changes in corticotropin-releasing factor and glucocorticoid receptor expression

Archival Report
Anhedonia Following Early-Life Adversity Involves Aberrant Interaction of Reward and Anxiety Circuits and Is Reversed by Partial Silencing of Amygdala Corticotropin-Releasing Hormone Gene