In mouse experiments, scientists introduced a specific type of recombinant protein to the site of a spinal cord injury where these cells, called pericytes, had flooded the lesion zone. Once exposed to this protein, results showed, pericytes change shape and inhibit the production of some molecules while secreting others, creating "cellular bridges" that support regeneration of axons -- the long, slender extensions of nerve cell bodies that transmit messages.

Researchers observed axon regrowth in injured mice that received a single treatment injection of the growth-factor protein, and the animals also regained movement in their hind limbs. An experiment involving human cells suggests the results are not restricted to mice.

"There's a lot more that can be learned and a lot that can be expanded, but the more we worked on this, the more stunned we really were by the potency of this single treatment and how effective it was," said senior study author Andrea Tedeschi, associate professor of neuroscience in The Ohio State University College of Medicine. "This finding goes beyond spinal cord injury -- it has implications in brain injury and stroke, and neurodegenerative diseases as well."

The work underscores how important blood vessel restoration is to recovery of neurological function after a spinal cord injury, researchers said.

"Spinal cord injuries are severe not only because they prevent transmission of information across the site of the injury, but because all of the vasculature structure and function is also compromised," said first study author Wenjing Sun, assistant professor of neuroscience at Ohio State. "Even if you are able to reestablish neuronal connectivity from one end to the other, the overall effect will still not be maximized unless you take care of everything else that falls apart."

The study was published April 18 in the journal Molecular Therapy.

Previous research suggesting pericytes interfere with spinal cord injury recovery had led some scientists to recommend clearing them from the lesion site to aid repair. But cancer research has indicated pericytes' properties change when they're exposed to a protein called platelet-derived growth factor BB (PDGF-BB) -- which is one way tumors generate their own blood supply. In cancer, the aim is to block PDGF-BB signaling.

Earlier neuroscience research also indicated that pericytes are highly "plastic," meaning they are very responsive to changes in the microenvironment -- including the presence of PDGF-BB. Tedeschi and colleagues saw potential to harness that cell-protein relationship to stabilize the vasculature surrounding a spinal cord injury. In the process, they found the newly sprouted blood vessels established a pathway for regenerated axons to follow.

Starting with imaging studies, the team showed that when a spinal cord is severed, pericytes migrate into the injury site over time but don't promote growth of functional blood vessels that are needed to support axon regeneration.

In cell-culture experiments, the researchers established a "carpet" of pericytes, added PDGF-BB, and then placed a layer of adult mouse sensory neurons on top and evaluated how much axons grew in 24 hours. The treated axons grew nearly as much as healthy axons extend under normal conditions.

PDGF-BB alone did not produce this result. Instead, experiments showed that pericytes combined with the growth factor rearranged fibronectin, a multifunctional adhesive glycoprotein that plays a critical role in tissue repair, cell attachment and motility. The cells themselves also change shape, becoming more elongated.

"We know these cells are going to infiltrate and deposit at the lesion epicenter. These elongated fiber structures that they become are far more permissive in promoting axons to regenerate from one end to the other and bypass the injury," Tedeschi said.

"To extend the clinical relevance of our findings, we cultured mouse neurons on top of human pericytes that were exposed to PDGF-BB, and that was sufficient to trigger a growth-promoting effect, suggesting that this might really be a generalized phenomenon that is not restricted to mice."

Turning to experiments in animals with spinal cord injury, researchers waited for seven days after the injury -- the equivalent of about nine months in a human adult -- before injecting a single dose of PDGF-BB at the injury site. Analysis of tissue four weeks after the injury showed that the PDGF-BB injection produced robust axon regenerative growth compared to the axon response in injured control mice.

"When we looked at formation of these pericyte structures that crossed the injury site, we saw the treatment promoted the growth of these bridges. And most if not all of these regenerating axons were able to escape the injury site by riding these cellular bridges that have formed in response to PDGF-BB administration," Sun said.

Electrophysiological and movement assessments of injured animals treated with PDGF-BB detected sensory activity beyond the lesion site and showed the mice regained better control of their hind limbs compared to control mice. The animals also were less sensitive to a non-painful stimulus, suggesting they did not experience the neuropathic pain that is often triggered by a spinal cord injury.

Analysis of the presence of inflammatory proteins during the repair process suggested that PDGF-BB administration not only promotes axon regeneration, but also reduces inflammation. RNA sequencing showed that spinal cord injury led to decreased gene expression by pericytes, but that the cells retained their core properties and did not convert into a different kind of cell -- for example, a cell type that could end up being destructive to the injury environment.

"There was a decrease in some classical pericyte markers, but a gain of some additional function linked to the attempt to rebuild cellular bridges and functional vessels," Sun said. "From the overall gene signature in our data, they're still classified as a pericyte."

Because Tedeschi, Sun and colleagues have previously shown in mice that gabapentin promotes regeneration of neural circuits after spinal cord injury, there's potential to consider a multipronged approach to therapy, Sun said.

"We could combine both -- modulating intrinsic properties of adult neurons with a drug, and what we are doing here, modulating the non-neuronal environment to produce cellular interactions that provide a more permissive substrate for the neuron to grow on," she said.

More work is planned to determine the precise timing for administration of PDGF-BB -- with the presumption that pericytes take some time to migrate to the injury -- as well as the ideal concentration of the treatment and a potential time-released delivery system.

This research was supported by the National Institute of Neurological Disorders and Stroke and Ohio State's Chronic Brain Injury Program.

Additional co-authors were Elliot Dion, Fabio Laredo, Allyson Okonak, Jesse Sepeda, Esraa Haykal, Min Zhou, Heithem El-Hodiri, Andy Fischer, Juan Peng and Andrew Sas, all of Ohio State, and Jerry Silver of Case Western Reserve University.

Men whose testosterone levels fall unusually high or unusually low for their age group face an increased risk of developing depression. A large study of middle-aged and older adults suggests that these hormonal imbalances serve as an indicator of mental health vulnerabilities, particularly for men in their early fifties. The findings were published in the Journal of Affective Disorders.

As men age, their reproductive systems undergo gradual physiological changes, most notably a steady decline in sex hormones. Research indicates that testosterone levels in men begin to decrease gradually around age 35. Total testosterone tends to drop by roughly half a percent each year. Other forms of the hormone can decline at a slightly faster rate of more than one percent annually.

Researchers Dan He, Huan Liu, Feng Zhang, and their colleagues at Xi’an Jiaotong University in China wanted to understand how this natural hormonal shift relates to psychological well-being. Past research has linked androgens to mood regulation because these hormones interact with brain chemicals like dopamine and serotonin. Most of that evidence has relied on data collected at a single moment in time. This makes it difficult to tell if hormonal changes actually precede the onset of mental health conditions.

The team focused on two specific measurements of the hormone. Total testosterone refers to all the testosterone currently circulating in the bloodstream. Most of this hormone is bound to proteins like albumin and sex hormone-binding globulin, rendering it largely inactive.

Free testosterone, on the other hand, is the tiny fraction that floats in the blood without binding to proteins. It usually makes up between one and three percent of a man’s total testosterone. Because it is unattached, free testosterone easily crosses cell membranes to bind with receptors and influence bodily functions directly. Many researchers consider it a more accurate measure of active hormones in the body.

To explore the connection between these hormone measures and mental health, the researchers analyzed health records from a massive database called the UK Biobank. The analysis included 133,733 men between the ages of 40 and 70. The researchers excluded anyone who already had a history of depression or anxiety at the beginning of the study.

The team also removed men who were taking anti-anxiety drugs, anti-depression medications, or any prescriptions known to alter testosterone levels. Men with pre-existing testicular dysfunction were excluded as well. This screening process helped ensure that the final analysis focused on individuals without pre-existing medical conditions that might skew the hormonal data.

The researchers looked at blood samples taken at the start of the project to determine each participant’s total and free testosterone levels. Rather than using a single threshold for high or low hormones, the team compared each man to other men in his specific five-year age bracket. They defined a hormonal imbalance as having levels substantially above or below the statistical average for that specific age group.

They then tracked the participants’ medical records over an average of nearly 11 years to see who eventually received a formal diagnosis of anxiety or depression. The researchers adjusted their statistical models to account for a wide variety of outside factors that can influence mood. These included body mass index, socioeconomic status, physical activity, smoking habits, alcohol consumption, and pre-existing conditions like heart disease, diabetes, chronic pain, and sleep issues.

Over the tracking period, 3,701 men developed depression and 3,398 developed anxiety. The researchers found that men with abnormally low and abnormally high total testosterone levels faced a greater risk of developing depression compared to men with average levels. High total testosterone carried an elevated risk, but the association was even stronger for the low end of the spectrum.

When looking at free testosterone, the link to depression was particularly pronounced. Men with unusually low free testosterone were about twice as likely to develop depression as those in the normal range. The researchers also found that low free testosterone was associated with a higher risk of developing both anxiety and depression simultaneously.

The researchers then broke the data down by specific age groups to see when these risks peaked. They observed that the link between hormonal imbalances and mood disorders was strongest in middle-aged men. For instance, in the 50 to 54 age group, low free testosterone was associated with roughly a fivefold increase in the risk of developing anxiety. In the 55 to 59 age group, low free testosterone was associated with more than triple the risk of depression.

The team mapped out the relationship visually and found a U-shaped curve for free testosterone in relation to mental health risks. This indicates that moving too far in either direction from the age-adjusted average carries an elevated risk for psychological issues. The researchers also noted that as men advanced into their late sixties, the association between high free testosterone and depression risk diminished.

In a separate analysis, the researchers looked at questionnaire scores that measure the severity of anxiety and depression symptoms. They found that low free testosterone was consistently associated with higher severity scores on both mental health assessments. These results suggest that free testosterone might serve as a sensitive biological marker for recognizing mood-related vulnerabilities during male aging.

The study relies on observational data, meaning it can only show a correlation. It does not prove that abnormal testosterone causes depression or anxiety. The hormone measurements were also only taken once at the beginning of the study. Because hormone levels naturally fluctuate throughout the day and over months or years, a single blood test might not capture a person’s long-term biological status.

The mental health diagnoses were based on hospital inpatient records. This reliance on official medical codes means the study might miss milder cases of depression or anxiety that are managed outside of clinical settings. The researchers also relied on self-reported questionnaires for lifestyle habits like smoking and drinking, which can sometimes introduce memory-related errors.

The deviations measured in the study represent statistical comparisons against a population average, not clinical diagnoses of testosterone deficiency. Experiencing a statistical imbalance does not mean a person requires medical treatment. The researchers emphasize that these results should not be used as a rationale for initiating testosterone replacement therapy. Such medical decisions rely on absolute clinical thresholds and the presence of physical symptoms, not just mathematical deviations from peer averages.

The researchers suggest that future studies with repeated hormone measurements could help map out long-term biological changes more accurately. They recommend that health professionals consider screening middle-aged men for mental health concerns if they exhibit signs of reproductive aging. Measuring free testosterone might offer an additional tool for identifying men who face a higher risk of mood disorders as they get older.

The study, “The complex relationship between testosterone imbalance and the risk of depression and anxiety in men,” was authored by Dan He, Yifan Gou, Wenming Wei, Chuyu Pan, Boyue Zhao, Jin Feng, Jingni Hui, Huan Liu, and Feng Zhang.