Biology subjects

Cole, J. D.

Publications and source records attributed to Cole, J. D..

4 recordsLinked to original sources

bioRxiv2019

Adult-born hippocampal neurons undergo extended development and are morphologically distinct from neonatally-born neurons

During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period, or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally-relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2-7 weeks neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites and more dendritic filopodia than all other groups. Indeed, between 7-24 weeks, adult-born neurons gained additional dendritic branches, grew a 2nd primary dendrite, acquired more mushroom spines and had enlarged mossy fiber presynaptic terminals. Compared to neonatally-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the lifespan, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatally-born neurons may additionally endow adult-born neurons with unique functions even after they have matured. SIGNIFICANCE STATEMENTNeurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats, and end up with distinct morphological features compared to neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates.

neuroscience↗

bioRxiv2019

Correlation between Retinal Ganglion Cell Loss and Nerve Crush Force-Impulse Established with an Instrumented Tweezers in Mice

ObjectivesRodent models of optic nerve crush (ONC) have often been used to study degeneration and regeneration of retinal ganglion cells (RGCs) and their axons as well as the underlying molecular mechanisms. However, ONC results from different laboratories exhibit a range of RGC injury with varying degree of axonal damage. We developed an instrumented tweezers to measure optic nerve (ON) crush forces in real time and studied the correlation between RGC axon loss and force-impulse, the product of force and duration, applied through the instrumented tweezers in mice.\n\nMethodsA pair of standard self-closing #N7 tweezers were instrumented with miniature foil strain gauges at optimal locations on both tweezer arms. The instrumented tweezers were capable of recording the tip closure forces in the form of voltages, which were calibrated through load cells to corresponding tip closure forces over the operating range. Using the instrumented tweezers, the ONs of multiple mice were crushed with varied forces and durations and the axons in the immunostained sections of the crushed ONs were counted.\n\nResultsWe found that the surviving axon density correlated with crush force, with longer duration and stronger crush forces producing consistently more axon damage.\n\nDiscussionThe instrumented tweezers enable a simple technique for measurement of ONC forces in real-time for the first time. Using the instrumented tweezers, experimenters can quantify crush forces during ONC to produce consistent and predictable post-crush cell death. This should permit future studies a way to produce nerve damage more consistently than is available now.

neuroscience↗

bioRxiv2019

Adult-born neurons inhibit developmentally-born neurons in the dentate gyrus

During hippocampal-dependent memory formation, sensory signals from the neocortex converge in the dentate gyrus. It is generally believed that the dentate gyrus decorrelates inputs in order to minimize interference between codes for similar experiences, often referred to as pattern separation. Emerging evidence from mouse models suggests that adult-born neurons exert an inhibitory influence on the dentate gyrus, which may be important for maintaining the sparse code that is needed to form precise memories. However, since the dentate gyrus is composed of a heterogeneous population of cells that are born throughout life, it is unclear if newborn neurons inhibit all cells equally. We therefore investigated whether adult neurogenesis in rats modulates activity in dentate gyrus neurons that are born at the peak of early postnatal development. Adult neurogenesis was increased by subjecting rats to an alternating running and memantine treatment schedule, and it was decreased with a transgenic GFAP-TK rat model. Activity was measured by quantifying experience-induced Fos expression in BrdU+ cells. Consistent with an inhibitory role, enhancing neurogenesis blocked experience-dependent Fos expression in developmentally-born neurons and also in the broader granule cell population. In contrast, blocking neurogenesis did not significantly impact activity patterns. These results confirm previous work in mice and identify the developmentally-born population of neurons as a major target of neurogenesis-mediated inhibition. Treatments that target neurogenesis may therefore benefit disorders that are characterized by excitation-inhibition imbalance in the hippocampus, such as age-related memory impairments, fear and anxiety, and epilepsy.

neuroscience↗

bioRxiv2018

Differential effects of extended exercise and memantine treatment on adult neurogenesis in male and female rats

The creation of new neurons in adulthood has potential for treating a number of disorders that are characterized by neurodegeneration or impaired plasticity. Animal models of reduced neurogenesis, and studies of the volume and structural integrity of the hippocampus in humans, suggest a possible therapeutic role for adult neurogenesis in age-related cognitive decline, depression, and schizophrenia. Research over the past 20 years has identified a number of approaches for enhancing adult neurogenesis, such as exercise, NMDA receptor antagonists, antidepressant drugs and environmental enrichment. However, despite the chronic nature of many disorders that impact the human hippocampus, most animal studies have only examined the efficacy of neurogenic treatments over relatively short timescales ([~]1 month or less). Additionally, investigations into the regulation of neurogenesis typically include only 1 sex, even though many disorders that affect the hippocampus differentially impact males and females. Here, we therefore tested whether two known pro-neurogenic treatments, running and the NMDA receptor antagonist, memantine, could lead to long-term increases in neurogenesis in male and female rats. We found that continuous access to a running wheel (cRUN) initially increased neurogenesis in both sexes, but effects were minimal after 1 month (both sexes) and completely absent after 5 months (males). Similarly, a single injection of memantine (sMEM) only transiently increased adult neurogenesis in both males and females. To determine whether extended increases in neurogenesis were possible with 2 months of RUN and MEM treatments, we subjected rats to interval running (iRUN), weekly memantine injections (mMEM), or combined treatments (iRUN-mMEM, mMEM-iRUN). We found that 2 months of iRUN increased DCX+ cell density in females but iRUN-mMEM treatment increased DCX+ cell density in males. However, analyses with thymidine analogs revealed that neurogenesis was minimally increased during the initial phases of the 2 month treatments. Collectively, our findings identify sex differences in the efficacy of neurogenic manipulations, which may be relevant for designing plasticity-promoting treatments that target the hippocampus.

neuroscience↗