One of the more common mental illnesses is also one of the hardest to precisely define, and for various reasons it is among the most difficult to treat successfully. Several research studies have estimated that between 1% and 3% of American adults suffer from borderline personality disorder (BPD)—at least 2 million adults and perhaps several times that number.

BPD can have a profound impact on a person’s ability to function, for its symptoms, while diverse and not all present at the same time, span a wide range: emotional instability, impulsiveness, hard-to-control anger, fear of abandonment, and difficulties with maintaining a sense of self. These take a serious toll on interpersonal relationships, tending to destabilize them and placing them in constant flux. There is also great internal anguish, often compounded by co-occurring depression, panic disorder, anxiety, or PTSD. Suicide risk in BPD patients is well above that in the general population.

Treatment of BPD is often difficult. Antidepressants as well as anti-anxiety and mood-stabilizing medicines have helped some patients. So have a number of forms of talk therapy, including dialectical behavioral therapy (DBT), transference-focused psychotherapy (TFP) and mentalization-based treatment (MBT).

Now, a team led by 2015 BBRF Young Investigator Ekaterina Likhtik, Ph.D., at Hunter College and the Neuroscience Collaborative at the Graduate Center, City University of New York, has set out to design an animal model of BPD, in order to provide a scientific basis for exploring its neural underpinnings in the human brain. The team’s hope is to inform efforts to design future BPD-specific treatments.

In the journal Psychopharmacology, Dr. Likhtik and colleagues recently described the cluster of BPD symptoms and considered how various existing animal models of psychiatric illnesses might pertain to them. They concluded that some of the primary BPD symptoms have indeed been replicated in rodent models for other disorders—such symptoms as “poor impulse control,” “unstable relationships,” and “instability of affect.”

To replicate the development of BPD in humans, the team proposes a “two-hit model,” in which rodents would be exposed, at different points in their development, to different environmental and social challenges. The first is early-life stress. Stress or trauma early in life is thought to be one of the potential triggers for some people with BPD, with potentially harmful impacts upon the body’s “HPA axis,” the trio of organs (the hypothalamus and the pituitary and adrenal glands) that regulate responses to stress and adversity. Early-life stress also alters communications between parts of the brain’s frontal cortex and emotion centers deep within the brain. Researchers have linked anomalies in these regions with problems in processing pain and gauging the emotional salience of events, extinguishing fear, and handling strong emotions like anger or rejection. All are relevant in BPD.

The mouse model of BPD proposed by Dr. Likhtik and colleagues introduces to this first “hit” a second “hit” that takes the form of mild stress during adulthood. Such stress, although in a stronger form, is also a staple in mouse models of other psychiatric disorders, including rodent models of depression, PTSD, and anxiety.

Noting that difficulties in interpersonal functioning “are a cardinal symptom” of BPD, the team proposes that the BPD-like rodents, having sustained the two “hits,” be given tests of social interaction in pairs and groups, in which their behavior—pre- and post-“hits”—can be studied.