Jesse Winters - Academia.edu (original) (raw)

Papers by Jesse Winters

Research paper thumbnail of Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats

Scientific Reports, 2020

Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-... more Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-specific epigenetic activity and catecholamine levels. We hypothesized that stress in adolescence would increase adult trauma vulnerability by impairing extinction-retention, a deficit in PTSD, by (1) altering class IIa histone deacetylases (HDACs), which integrate effects of stress on gene expression, and (2) enhancing norepinephrine in brain regions regulating cognitive effects of trauma. We investigated the effects of adolescent-stress on adult vulnerability to severe stress using the single-prolonged stress (SPS) model in male rats. Rats were exposed to either (1) adolescent-stress (33–35 postnatal days) then SPS (58–60 postnatal days; n = 14), or (2) no adolescent-stress and SPS (58–60 postnatal days; n = 14), or (3) unstressed conditions (n = 8). We then measured extinction-retention, norepinephrine, HDAC4, and HDAC5. As expected, SPS exposure induced an extinction–retention defici...

Research paper thumbnail of Form and Function in the Scn1b-null Cerebellar Cortex: Implications for EpilepticEncephalopathy

Research paper thumbnail of The temporally-integrated causality landscape: A theoretical framework for consciousness and meaning

Consciousness and Cognition

Research paper thumbnail of The Temporally-Integrated Causality Landscape: Reconciling Neuroscientific Theories With the Phenomenology of Consciousness

Frontiers in Human Neuroscience

In recent years, there has been a proliferation of neuroscientific theories of consciousness. The... more In recent years, there has been a proliferation of neuroscientific theories of consciousness. These include theories which explicitly point to EM fields, notably Operational Architectonics and, more recently, the General Resonance Theory. In phenomenological terms, human consciousness is a unified composition of contents. These contents are specific and meaningful, and they exist from a subjective point of view. Human conscious experience is temporally continuous, limited in content, and coherent. Based upon those phenomenal observations, pre-existing theories of consciousness, and a large body of experimental evidence, I derived the Temporally-Integrated Causality Landscape (TICL). In brief, the TICL proposes that the neural correlate of consciousness is a structure of temporally integrated causality occurring over a large portion of the thalamocortical system. This structure is composed of a large, integrated set of neuronal elements (the System), which contains some subsystems, d...

Research paper thumbnail of Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats

Behavioural Brain Research

Research paper thumbnail of Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats

Behavioural Brain Research

Research paper thumbnail of Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J

PLoS Genetics, 2011

CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositi... more CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/ SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 56 higher than endogenous Fig4 completely rescued lethality, whereas 26 expression gave only partial rescue, providing a model of the human disease. The level of FIG4-I41T protein in transgenic tissues is only 2% of that predicted by the transcript level, as a consequence of the protein instability caused by impaired interaction of the mutant protein with VAC14. Analysis of patient fibroblasts demonstrated a comparably low level of mutant I41T protein. The abundance of FIG4-I41T protein in cultured cells is increased by treatment with the proteasome inhibitor MG-132. The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. The transgenic model will be useful for testing in vivo interventions to increase the abundance of the mutant protein.

Research paper thumbnail of Congenital CNS Hypomyelination in the Fig4 Null Mouse Is Rescued by Neuronal Expression of the PI(3,5)P2 Phosphatase Fig4

Journal of Neuroscience, 2011

The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor... more The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor, hypopigmentation, spongiform degeneration of the brain, and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. In humans, the missense mutation FIG4 I41T combined with a FIG4 null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show that Fig4 null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller-caliber axons lack myelin sheaths entirely, whereas many large-and intermediate-caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In the Fig4 null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution, but the number of myelinating OLs is greatly compromised. The total number of axons in the Fig4 null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression of Fig4, demonstrating a non-cell-autonomous function of Fig4 in OL maturation and myelin development. In transgenic mice with global overexpression of the human pathogenic FIG4 variant I41T, there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4 I41T mutant protein.

Research paper thumbnail of Repeated stress exposure in mid-adolescence attenuates behavioral, noradrenergic, and epigenetic effects of trauma-like stress in early adult male rats

Scientific Reports, 2020

Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-... more Stress in adolescence can regulate vulnerability to traumatic stress in adulthood through region-specific epigenetic activity and catecholamine levels. We hypothesized that stress in adolescence would increase adult trauma vulnerability by impairing extinction-retention, a deficit in PTSD, by (1) altering class IIa histone deacetylases (HDACs), which integrate effects of stress on gene expression, and (2) enhancing norepinephrine in brain regions regulating cognitive effects of trauma. We investigated the effects of adolescent-stress on adult vulnerability to severe stress using the single-prolonged stress (SPS) model in male rats. Rats were exposed to either (1) adolescent-stress (33–35 postnatal days) then SPS (58–60 postnatal days; n = 14), or (2) no adolescent-stress and SPS (58–60 postnatal days; n = 14), or (3) unstressed conditions (n = 8). We then measured extinction-retention, norepinephrine, HDAC4, and HDAC5. As expected, SPS exposure induced an extinction–retention defici...

Research paper thumbnail of Form and Function in the Scn1b-null Cerebellar Cortex: Implications for EpilepticEncephalopathy

Research paper thumbnail of The temporally-integrated causality landscape: A theoretical framework for consciousness and meaning

Consciousness and Cognition

Research paper thumbnail of The Temporally-Integrated Causality Landscape: Reconciling Neuroscientific Theories With the Phenomenology of Consciousness

Frontiers in Human Neuroscience

In recent years, there has been a proliferation of neuroscientific theories of consciousness. The... more In recent years, there has been a proliferation of neuroscientific theories of consciousness. These include theories which explicitly point to EM fields, notably Operational Architectonics and, more recently, the General Resonance Theory. In phenomenological terms, human consciousness is a unified composition of contents. These contents are specific and meaningful, and they exist from a subjective point of view. Human conscious experience is temporally continuous, limited in content, and coherent. Based upon those phenomenal observations, pre-existing theories of consciousness, and a large body of experimental evidence, I derived the Temporally-Integrated Causality Landscape (TICL). In brief, the TICL proposes that the neural correlate of consciousness is a structure of temporally integrated causality occurring over a large portion of the thalamocortical system. This structure is composed of a large, integrated set of neuronal elements (the System), which contains some subsystems, d...

Research paper thumbnail of Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats

Behavioural Brain Research

Research paper thumbnail of Functional deficit in hippocampal activity during fear extinction recall in the single prolonged-stress model of PTSD in male rats

Behavioural Brain Research

Research paper thumbnail of Pathogenic Mechanism of the FIG4 Mutation Responsible for Charcot-Marie-Tooth Disease CMT4J

PLoS Genetics, 2011

CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositi... more CMT4J is a severe form of Charcot-Marie-Tooth neuropathy caused by mutation of the phosphoinositide phosphatase FIG4/ SAC3. Affected individuals are compound heterozygotes carrying the missense allele FIG4-I41T in combination with a null allele. Analysis using the yeast two-hybrid system demonstrated that the I41T mutation impairs interaction of FIG4 with the scaffold protein VAC14. The critical role of this interaction was confirmed by the demonstration of loss of FIG4 protein in VAC14 null mice. We developed a mouse model of CMT4J by expressing a Fig4-I41T cDNA transgene on the Fig4 null background. Expression of the mutant transcript at a level 56 higher than endogenous Fig4 completely rescued lethality, whereas 26 expression gave only partial rescue, providing a model of the human disease. The level of FIG4-I41T protein in transgenic tissues is only 2% of that predicted by the transcript level, as a consequence of the protein instability caused by impaired interaction of the mutant protein with VAC14. Analysis of patient fibroblasts demonstrated a comparably low level of mutant I41T protein. The abundance of FIG4-I41T protein in cultured cells is increased by treatment with the proteasome inhibitor MG-132. The data demonstrate that FIG4-I41T is a hypomorphic allele encoding a protein that is unstable in vivo. Expression of FIG4-I41T protein at 10% of normal level is sufficient for long-term survival, suggesting that patients with CMT4J could be treated by increased production or stabilization of the mutant protein. The transgenic model will be useful for testing in vivo interventions to increase the abundance of the mutant protein.

Research paper thumbnail of Congenital CNS Hypomyelination in the Fig4 Null Mouse Is Rescued by Neuronal Expression of the PI(3,5)P2 Phosphatase Fig4

Journal of Neuroscience, 2011

The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor... more The plt (pale tremor) mouse carries a null mutation in the Fig4(Sac3) gene that results in tremor, hypopigmentation, spongiform degeneration of the brain, and juvenile lethality. FIG4 is a ubiquitously expressed phosphatidylinositol 3,5-bisphosphate phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. In humans, the missense mutation FIG4 I41T combined with a FIG4 null allele causes Charcot-Marie-Tooth 4J disease, a severe form of peripheral neuropathy. Here we show that Fig4 null mice exhibit a dramatic reduction of myelin in the brain and spinal cord. In the optic nerve, smaller-caliber axons lack myelin sheaths entirely, whereas many large-and intermediate-caliber axons are myelinated but show structural defects at nodes of Ranvier, leading to delayed propagation of action potentials. In the Fig4 null brain and optic nerve, oligodendrocyte (OL) progenitor cells are present at normal abundance and distribution, but the number of myelinating OLs is greatly compromised. The total number of axons in the Fig4 null optic nerve is not reduced. Developmental studies reveal incomplete myelination rather than elevated cell death in the OL linage. Strikingly, there is rescue of CNS myelination and tremor in transgenic mice with neuron-specific expression of Fig4, demonstrating a non-cell-autonomous function of Fig4 in OL maturation and myelin development. In transgenic mice with global overexpression of the human pathogenic FIG4 variant I41T, there is rescue of the myelination defect, suggesting that the CNS of CMT4J patients may be protected from myelin deficiency by expression of the FIG4 I41T mutant protein.