Dataset Information

Traumatic Life Experiences During Critical Periods Lead to Diverse Developmental Trajectories

ABSTRACT: Proper neurodevelopment relies on how life experiences influence the biology of an individual. This influence is pivotal during critical periods, which are time windows characterized by enhanced responsiveness to environmental stimuli. Positive experiences during these critical periods lead to healthy brain wiring and development of proper behavioral skills. Conversely, diverse traumatic events (e.g., physical/sexual abuse, prolonged hospitalization, warfare) can impair brain development, increasing risk for neuropsychiatric disorders. Whether a correspondence between specific traumas and the insurgence of certain neuropsychiatric traits exists remains elusive, suggesting that a particular traumatic event can trigger different psychiatric consequences. Here, we examined the long-term consequences of two different adverse life events (exposure to a predator scent or underwater immersion) in distinct developmental periods: infancy, childhood, adolescence, or young adulthood in wild type mice. We found specific alterations at both behavioral and molecular/cellular levels in adulthood in response to traumas experienced at different earlier developmental stages, suggesting a crucial role played by the timing (and not the type) of stress in shaping long-term effects. A parallel analysis in individuals exposed to traumatic life events revealed analogous results, highlighting the translational value of our findings. Finally, our data suggested BDNF pathway as a promising therapeutic target to ameliorate psychopathology related to trauma in early adulthood in mice and potentially also in individuals. Overall, our results point to the existence of critical periods for trauma exposure that differentially modulate the adult behavioral outcomes and induce time-specific molecular/cellular patterns in the brain, which may have therapeutic implications.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Martina Bartolucci

LAB HEAD: Andrea Petretto

PROVIDER: PXD054552 | Pride | 2026-06-29

REPOSITORIES: Pride

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Traumatic life experiences during critical periods lead to diverse developmental trajectories.

Morelli Giovanni G Visintin Greta G Gelli Elisa E Serani Angelo A Bartolucci Martina M Uccella Sara S D'Apruzzo Maria M Preiti Deborah D Chellali Mariam Marie MM Cucinelli Alessandra A Rastogi Mohit M Falappa Matteo M Scalabrini Andrea A Turecki Gustavo G Petretto Andrea A Tucci Valter V Cancedda Laura L

Cell reports. Medicine 20260512 6

Traumatic events can disrupt neurodevelopment, increasing the risk for neuropsychiatric disorders. However, the relationships between specific types of traumas and the emergence of particular neuropsychiatric traits remain elusive. Here, we examine the long-term consequences of different life-threatening events experienced during four distinct developmental periods in mice. Our findings at the behavioral and molecular/cellular levels in adulthood suggest a crucial role for timing (rather than ty ...[more]

PMID: 42127906

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Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.

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