Role of the amygdala-prefrontal network in the emergence of anxiety across childhood and adolescence: Impact of early life adversity in a nonhuman primate model – Anxiomonk

The project established a unique cohort of 21 rhesus macaques reared under different early social conditions (mother-, peer-, and surrogate-reared) and followed longitudinally across three developmental stages (2.5, 3.5, 5 years). Socio-emotional outcomes were assessed with:

Ethological monitoring of daily social interactions;

Experimental paradigms such as the Human Intruder task (emotion regulation), A-not-B (executive function), and attention bias to facial gestures (socio-emotional processing).

Neuroimaging included:

Structural MRI for grey and white matter maturation;

Diffusion Tensor Imaging (DTI) for white matter microstructure;

Resting-state fMRI for functional connectivity.

Analyses targeted prefrontal, parietal, amygdala, and striatal circuits. Methodological challenges such as motion and anesthesia sensitivity required the refinement of acquisition protocols and the development of tailored analysis pipelines.

From a methodological perspective, we implemented a high-resolution diffusion MRI sequence that we specifically developed and validated for this project. This tailored sequence is particularly advantageous for longitudinal monitoring of the macaque brain, given its smaller size compared to the human brain. Leveraging this approach, we successfully acquired diffusion MRI data in juvenile macaques at an unprecedented isotropic resolution of 0.8 mm, providing the sensitivity required for precise assessment of brain tissue microstructure over time.

Bihan-Poudec Y, Tounekti S, Troalen T, Rayson H, Froesel M, Lamberton F, Zariry Z, Gacoin M, Richard N, Hamed SB, Hiba B. Cardiovascular effects on high-resolution 3D multi-shot diffusion MRI of the rhesus macaque brain. Imaging Neurosci (Camb). 2023 Dec 8;1:imag-1-00039. doi: 10.1162/imag_a_00039. PMID: 40799687; PMCID: PMC12007547.

Behaviorally, early adversity altered socio-emotional trajectories. Rayson et al. (2021, Sci Rep) showed stronger attention bias to threat and reduced bias to affiliative cues in ESA monkeys, linked to higher anxiety and lower social engagement. Massera et al. (2023, Proc R Soc B) demonstrated that ESA animals had impaired emotion regulation strategies across development, with executive inflexibility predicting poor regulation and anxiety escalation.

Preliminary neuroimaging results indicate altered brain maturation in ESA monkeys. Structural MRI revealed group differences in cortical thickness (PFC, OFC, PPC) and subcortical volumes (amygdala, striatum). DTI showed atypical white matter trajectories (cingulum, ACR, ALIC). Importantly, larger amygdala/striatum volumes predicted poor ER, whereas higher FA in cingulum and SLF predicted better outcomes.

Together, results reveal that early adversity disrupts cortical–subcortical integration, leading to long-term socio-emotional vulnerability.

The outstanding feature of Anxiomonk is its unique dataset, combining longitudinal ethological and multimodal imaging data in non-human primates—a resource without equivalent worldwide. This integrated approach bridges animal models and human psychopathology, providing unprecedented insights into sensitive developmental periods and brain–behavior mechanisms of early adversity.

Future work builds directly on this foundation. The new ANR project Sociomonk explores how early adversity impacts neuromodulatory systems, focusing on oxytocinergic and noradrenergic pathways, integrating hormonal assays with imaging. In parallel, touchscreen-based testing systems installed in the colony will allow high-throughput and ecologically valid assessment of socio-cognitive functions. These perspectives strengthen translational relevance and open the way toward preventive interventions in at-risk youth.

Characterized by extreme and persistent fear, worry, and/or the avoidance of perceived threats, anxiety disorders are one of the most prevalent forms of psychiatric disorder. These disorders have an extremely negative impact on quality of life, and currently rank in the top ten contributors to global disability. Critically, anxiety disorders often have an early onset and run a chronic course, with childhood and adolescence having been identified as the core period of developmental risk. If left untreated, anxiety in this period can lead to numerous behavioural and socio-emotional difficulties, as well as substance abuse and long-term mental health problems. Clearly, elucidating the developmental trajectories and aetiology of anxiety in early life is therefore critical. The proposed project will utilize a nonhuman primate model to investigate both neurobiological and psychological mechanisms through which anxiety may emerge and be maintained across early development, and will address three main unanswered questions: i) how does the development of brain regions and connectivity associated with anxiety disorders relate to levels of anxiety across childhood, adolescence, and into adulthood; ii) how is an attention bias towards threat (ABT) linked to changes in the brain and anxiety during this period; and iii) how does atypical early social experience modulate the relationships between brain development, ABT, and anxiety? To achieve this, brain imaging (anatomical MRI and diffusion MRI), observational, and behavioural assessments will be conducted longitudinally (2.5, 3.5, and 4.5 years of age) with a group of rhesus macaque monkeys (n = 22). Notably, the specific group of macaques to be included in this project offers an exciting opportunity to determine how differences in the early social environment affect the emergence of anxiety in a very well-controlled manner, as half of them were reared by their mothers (n = 11) and half (n = 11) were reared in a nursery of peers. This population is the only one of its kind in Europe, and at the start of the project, animals will be of an age equivalent to late childhood in humans (2.5 years). Results from this novel research project, which combines a number of techniques and involves the integration of interdisciplinary knowledge (neuroscience, psychology, and ethology), will provide important and unique insights into the mechanisms underlying the emergence and maintenance of early anxiety. Furthermore, the more complex and nuanced understanding afforded by the proposed project can guide future research with humans, and consequently, may aid the design of more effective treatments and preventative interventions targeting younger populations.