PROJECT SUMMARY
Lower Urinary Tract Symptoms (LUTS) are among the most common reasons to see a urologist across the
lifespan and are often accompanied by psychological consequences, such as anxiety and depression.
Patients with LUTS may have a disrupted bladder–brain dialogue; they may say “I don’t even feel anything
until I am wet”. Better therapeutic options can emerge from a better understanding of the fundamental brain
circuits and cells that contribute to LUTS and that contribute to bladder–brain communication. A potential LUTS
etiology that merits closer study is early life urinary tract infection (UTI). Clinical studies in females (who have
UTIs 4x more often than males) show early life UTIs predict later life LUTS. Basic research on UTIs and other
bladder insults in adulthood suggest inflammation underlies acute LUTS and psychological consequences. For
example, adult systemic injection of cyclophosphamide (CYP) — the most common noninvasive (catheter-free)
way to model UTI-linked inflammation — leads to bladder and psychobehavioral dysfunction. However, there is
a striking absence of research on the role of early life UTIs in later life LUTS and psychological consequences.
Here we show for the first time that female mice experiencing repeated, early life cystitis after CYP have
bladder and psychobehavioral dysfunction in adulthood. These data fuel our hypotheses: Early life
CYP-induced cystitis induces bladder and brain inflammation, which disrupts bladder-brain dialogue and leads
to lifelong LUTS and psychobehavioral consequences; this later life bladder and brain dysfunction can be
reversed by manipulation of key brain circuits in adulthood. In Aim 1, we will define early life CYP-induced
inflammatory indices in bladder and brain across the lifespan. In Aim 2, we will determine early-life
CYP-induced functional changes in bladder and brain across the lifespan, launching off from our pilot data:
repeated, early-life CYP-induced cystitis leads to adulthood voiding dysfunction and anxiety-like behavior. We
will use pharmacologic tools to address the mechanism and specificity of these functional changes, and test for
anxiety- and depression-like phenotypes throughout life. In Aim 3, we will map and manipulate key
components of the brain circuits that contribute to bladder-brain dialogue. Using our proven abilities to assess
neuron activity in brain regions central to this dialogue (locus coeruleus, Barrington’s nucleus, frontal cortex),
we will record the activity of sets of neurons in freely-moving mice before and after voiding events in our early
life CYP model. We hypothesize that early life cystitis disrupts the ability of these neuron types to respond to
sensation from the bladder and thus discriminate voiding cycle stages. We will then attempt to reverse the
early life cystitis-induced bladder and psychobehavioral dysfunction in later life by optogenetically manipulating
the activity of relevant neurons in adulthood, as we have already done in adult models. Given the prevalence of
LUTS, the basic experiments proposed here have enormous potential to expand our understanding of how
neonatal cystitis influences the bladder-brain dialogue throughout the lifespan.
