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Anxious parents are likely to have anxious children. This is true of rhesus monkeys as well as humans. Researchers at the University of Wisconsin, Madison utilized positron emission topography (PET) scans to study anxiety in multiple generations of rhesus monkeys. Findings indicated that the inheritance of an over-active brain circuit might set the stage for the development of anxiety or depressive disorders. The study was discussed in a recent issue of NeuroScientistNews: 

 

In rhesus monkey families -- just as in their human cousins -- anxious parents are more likely to have anxious offspring. And a new study in an extended family of monkeys provides important insights into how the risk of developing anxiety and depression is passed from parents to children.

 

The study from the Department of Psychiatry and the Health Emotions Research Institute at the University of Wisconsin-Madison shows how an over-active brain circuit involving three brain areas inherited from generation to generation may set the stage for developing anxiety and depressive disorders.

 

The study is published online in the early edition of the Proceedings of the National Academy of Sciences. It shows that elevated activity in this prefrontal- limbic -midbrain circuit is likely involved in mediating the in-born risk for extreme anxiety, anxious temperament that can be observed in early childhood.

 

"Over-activity of these three brain regions are inherited brain alterations that are directly linked to the later life risk to develop anxiety and depression,'' says senior author Dr. Ned Kalin, chair of psychiatry at the UW School of Medicine and Public Health. "This is a big step in understanding the neural underpinnings of inherited anxiety and begins to give us more selective targets for treatment."

 

Previous research by Kalin's group has shown that anxious temperament is inherited, and explained the brain circuits involved. About half of children who show extreme anxiety go on to develop stress-related psychiatric disorders later in life.

 

Monkeys, like humans, can be temperamentally anxious and pass their anxiety-related genes on to the next generation.

 

By studying nearly 600 young rhesus monkeys from a large multi-generational family, Drs. Andrew Fox, Kalin, and colleagues found that about 35 percent of variation in anxiety-like tendencies is explained by family history.

 

To understand which brain regions are responsible for passing anxiety from generation to generation, the authors measured anxiety-related behavior with high-resolution functional and structural brain imaging. They exposed the young monkeys to a mildly threatening situation that a child would also encounter, exposure to a stranger who does not make eye contact with the monkey. During this encounter, they used imaging methods commonly used in humans (positron emission tomography, PET) to identify brain regions in which increased metabolism predicted each individual's level of anxiety.

 

By closely examining how individual differences in brain function and anxiety-related behavior fall through the family tree, the authors identified brain systems responsible for the parent-to-child transmission of anxiety-related behavior. Using this "genetic correlation" approach, the authors found the neural circuit where metabolism and an early-life anxious temperament are likely to share the same genetic basis.

 

Interestingly, the brain circuit that was genetically correlated with individual differences in early-life anxiety involved three survival-related brain regions. These regions were located in the brain stem, the most primitive part of the brain; the amygdala, the limbic brain fear center; and the prefrontal cortex, which is responsible for higher-level reasoning and is fully developed only in humans and their primate cousins.

 

"Basically, we think that to a certain extent, anxiety can provide an evolutionary advantage because it helps an individual recognize and avoid danger, but when the circuits are over-active, it becomes a problem and can result in anxiety and depressive disorders," Kalin explains.

 

Surprisingly, these studies found that it was the function of these brain structures -- and not their size -- that was responsible for the genetic transfer of an anxious temperament. Although the search for the genetic underpinnings of anxiety have thus far been elusive, this research helps explain how genes might affect brain function and lead to extreme childhood anxiety, which greatly increases the risk to develop anxiety and depressive disorders.

 

"Now that we know where to look, we can develop a better understanding of the molecular alterations that give rise to anxiety-related brain function,'' Kalin says. "Our genes shape our brains to help make us who we are."

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Why are some resilient to chronic stress and not others. Findings from a recent animal study of chronic social defeat stress sheds light on the neurocircuitry involved in vulnerability or resiliency to stress. NeuroScientistNews discussed the study in a recent article:  

Humans are remarkably resilient when confronted with tremendous amounts of stress and trauma. While most people are able to maintain balanced psychological and physical functioning, some people are vulnerable, or susceptible, to the negative biological, psychological, and social consequences of stress. The biological factors underlying susceptibility are unknown and likely intersect with an individual’s ability to cope, among other factors.

 

Emerging evidence from animal studies suggests there are distinct cellular and molecular adaptations that occur in response to stress to either promote resiliency or lead to susceptibility. The ventral striatum (vSTR) has been identified as a key brain region for regulating depression-related behaviors following chronic stress. In a recent study, Christoffel et al. elucidated the specific inputs to the vSTR mediating susceptibility to stress in mice following chronic social defeat stress (CSDS). CSDS is a well-validated model for studying the cellular and molecular underpinnings of stress-related psychiatric diseases in rodents.

 

The CSDS paradigm consists of pairing an experimental C57BL/6J mouse with an aggressive, CD-1 retired breeder mouse over the course of days in a cage. After each daily pairing, these mice are housed in the same cage, only separated by a partition with holes to allow for continuous ‘psychological’ stress for the experimental mouse from sensory interaction with the aggressor mouse. Following CSDS, the experimental mice are tested in the social interaction behavioral assay to assess the degree of social avoidance (i.e., anxiety and depression related behavior). The experimental mouse is placed into an open arena with the caged aggressor mouse and the amount of time spent socially interacting is recorded. Despite experiencing the same defeat stressor, experimental mice can be separated into ‘susceptible’ or ‘resilient’ groups to study the biological mechanisms contributing to these divergent phenotypes.

 

The authors used complementary approaches to identify and manipulate specific excitatory, glutamatergic inputs to the vSTR that mediate stress susceptibility. Projection-based viral targeting techniques revealed increased excitatory synaptic strength from the intralaminar (ILT) to the vSTR only in susceptible mice, whereas excitatory strength of the inputs to the vSTR from the prefrontal cortex (PFC) was similar between resilient and susceptible mice, suggesting enhanced ILT-vSTR signaling is relevant for stress-induced susceptibility.

 

Interestingly, inhibition of the ILT presynaptic inputs to the vSTR either by chronically inhibiting calcium release using viral-mediated expression of ‘tToxins’ or acutely by physiologically relevant optogenetic inhibition prevented stress-induced susceptibility, which was accompanied by reductions in excitatory postsynaptic currents (EPSCs) and the density of immature stubby dendritic spines of vSTR medium spiny neurons (MSNs).

 

In contrast, chronic inhibition of PFC-vSTR pathways further decreased stress-induced social interaction times and increased the density of stubby dendritic spines in the vSTR. However, acute, rapid optogenetic inhibition of this circuit had no effect on the susceptibility phenotype, suggesting sustained inhibition may be required, or other PFC efferents are responsible for promoting normal behavioral function (i.e., resiliency).

 

Human imaging findings indicate reduced vSTR response to various rewarding stimuli in individuals with major depressive disorder1,2,3, which are further supported by studies using deep brain stimulation of the internal capsule (includes vSTR) to alleviate symptoms of depression4. The present findings suggest that distinct glutamatergic pathways converge on the vSTR reward circuitry to mediate stress-induced susceptibility or promote resiliency. Animal studies are beginning to shed light on how stress leads to alterations in activity of particular neural circuits that could be relevant for many psychiatric diseases.

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