Theology or therapy? In what sense does depression exist?

Peer reviewed

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference

Cocaine blocks uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET). Cocaine reward/reinforcement has been linked to actions at DAT or to blockade of SERT. However, knockouts of neither DAT, SERT, or NET reduce cocaine reward/reinforcement, leaving substantial uncertainty about cocaine's molecular mechanisms for reward. Conceivably, the molecular bases of cocaine reward might display sufficient redundancy that either DAT or SERT might be able to mediate cocaine reward in the other's absence. To test this hypothesis, we examined double knockout mice with deletions of one or both copies of both the DAT and SERT genes. These mice display viability, weight gain, histologic features, neurochemical parameters, and baseline behavioral features that allow tests of cocaine influences. Mice with even a single wild-type DAT gene copy and no SERT copies retain cocaine reward/reinforcement, as measured by conditioned place-preference testing. However, mice with no DAT and either no or one SERT gene copy display no preference for places where they have previously received cocaine. The serotonin dependence of cocaine reward in DAT knockout mice is thus confirmed by the elimination of cocaine place preference in DAT/SERT double knockout mice. These results provide insights into the brain molecular targets necessary for cocaine reward in knockout mice that develop in their absence and suggest novel strategies for anticocaine medication development.

Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease.

Mutations in the human phosphofructokinase muscle subunit gene (PFKM) are known to cause myopathy classified as glycogenosis type VII (Tarui disease). Previously described molecular defects include base substitutions altering encoded amino acids or resulting in abnormal splicing. We report a mutation resulting in phosphofructokinase deficiency in three patients from an Ashkenazi Jewish family. Using a reverse transcription PCR assay, PFKM subunit transcripts differing by length were detected in skeletal muscle tissue of all three affected subjects. In the longer transcript, an insertion of 252 nucleotides totally homologous to the structure of the 10th intron of the PFKM gene was found separating exon 10 from exon 11. In addition, two single base transitions were identified by direct sequencing: [exon 6; codon 95; CGA (Arg) to TGA (stop)] and [exon 7; codon 172; ACC (Thr) to ACT (Thr)] in either transcript. Single-stranded conformational polymorphism and restriction enzyme analyses confirmed the presence of these point substitutions in genomic DNA and strongly suggested homozygosity for the pathogenic allele. The nonsense mutation at codon 95 appeared solely responsible for the phenotype in these patients, further expanding genetic heterogeneity of Tarui disease. Transcripts with and without intron 10 arising from identical mutant alleles probably resulted from differential pre-mRNA processing and may represent a novel message from the PFKM gene.

Decreased brain reward produced by ethanol withdrawal.

Abstinence from chronic administration of various drugs of abuse such as ethanol, opiates, and psychostimulants results in withdrawal syndromes largely unique to each drug class. However, one symptom that appears common to these withdrawal syndromes in humans is a negative affective/motivational state. Prior work in rodents has shown that elevations in intracranial self-stimulation (ICSS) reward thresholds provide a quantitative index that serves as a model for the negative affective state during withdrawal from psychostimulants and opiates. The current study sought to determine whether ICSS threshold elevations also accompany abstinence from chronic ethanol exposure sufficient to induce physical dependence. Rats prepared with stimulating electrodes in the lateral hypothalamus were trained in a discrete-trial current-intensity ICSS threshold procedure; subsequently they were subjected to chronic ethanol administration in ethanol vapor chambers (average blood alcohol level of 197 mg/dl). A time-dependent elevation in ICSS thresholds was observed following removal from the ethanol, but not the control, chambers. Thresholds were significantly elevated for 48 hr after cessation of ethanol exposure, with peak elevations observed at 6-8 hr. Blood alcohol levels were directly correlated with the magnitude of peak threshold elevation. Ratings of traditional overt signs of withdrawal showed a similar time course of expression and resolution. The results suggest that decreased function of reward systems (elevations in reward thresholds) is a common element of withdrawal from chronic administration of several diverse classes of abused drugs.

Grasshopper crop and midgut extract effects on plants: an example of reward feedback.

Acid extracts and a resultant fraction from solid-phase extraction (SPE) of Romalea guttata crop and midgut tissues induce sorghum (Sorghum bicolor var. Rio) coleoptile growth in 24-h incubations an average of 49% above untreated controls. When combined with plant auxin, indole-3-acetic acid (IAA), the SPE fraction shows a synergistic reaction, yielding increases in coleoptile growth that average 295% above untreated controls and 8% above IAA standards. The interaction lowered the point of maximum sensitivity of IAA 3 orders of magnitude, resulting in a new IAA physiological set point at 10(-7) g/ml. This synergism suggests that contents in animal regurgitants making their way into plant tissue during feeding may produce a positive feedback in plant growth and development following herbivory. Such a process, also known as reward feedback, may exert major controls on ecosystem-level relationships in nature.

Constructing a Neuroscientific Pastoral Theology of Fear and Hope

Contemporary therapeutic circles utilize the concept of anxiety to describe a variety of disorders. Emotional reductionism is a detriment to the therapeutic community and the persons seeking its help. This dissertation proposes that attention to the emotion of fear clarifies our categorization of particular disorders and challenges emotional reductionism. I propose that the emotion of fear, through its theological relationship to hope, is useful in therapeutic practice for persons who experience trauma and PTSD. I explore the differences between fear and anxiety by deconstructing anxiety. Through this process, I develop four categories which help the emotion of fear stand independent of anxiety in therapy. Temporality, behaviors, antidote and objects are categories which distinguish fear from anxiety. Together, they provide the impetus to explore the emotion of fear. Understanding the emotion of fear requires an examination of its neurophysiological embodiment. This includes the brain structures responsible for fear production, its defensive behaviors and the evolutionary retention of fear. Dual inheritance evolutionary theory posits that we evolved physically and culturally, helping us understand the inescapability of fear and the unique threats humans fear. The threats humans react to develop through subjective interpretations of experience. Sometimes threats, through their presence in our memories and imaginations, inhibit a person's ability to live out a preferred identity and experience hope. Understanding fear as embodied and subjective is important. Process theology provides a religious framework through which fear can be interpreted. In this framework, fear is developed as an adaptive human response. Moreover, fear is useful to the divine-human relationship, revealing an undercurrent of hope. In the context of the divine-human relationship fear is understood as an initial aim which protects a person from a threat, but also preserves them for novel future relationships. Utilizing a "double-listening" stance, a therapist hears the traumatic narrative and counternarratives of resistance and resilience. These counternarratives express an orientation towards hopeful futures wherein persons thrive through living out a preferred identity. A therapeutic practice incorporating the emotion of fear will utilize the themes of survival, coping and thriving to enable persons to place their traumatic narrative within their meaning systems.

The Jewish Law Firm: Past and Present

The rise and growth of large Jewish law firms in New York City during the second half of the twentieth century was nothing short of an astounding success story. As late as 1950, there was not a single large Jewish law firm in town. By the mid-1960s, six of the largest twenty law firms were Jewish, and by 1980, four of the largest ten prestigious law firms were Jewish firms. Moreover, the accomplishment of the Jewish firms is especially striking because, while the traditional large White Anglo-Saxon Protestant law firms grew at a fast rate during this period, the Jewish firms grew twice as fast, and they did so in spite of experiencing explicit discrimination. What happened? This book chapter is a revised, updated study of the rise and growth of large New York City Jewish law firms. It is based on the public record, with respect to both the law firms themselves and trends in the legal profession generally, and on over twenty in-depth interviews with lawyers who either founded and practiced at these successful Jewish firms, attempted and failed to establish such firms, or were in a position to join these firms but decided instead to join WASP firms. According to the informants interviewed in this chapter, while Jewish law firms benefited from general decline in anti-Semitism and increased demand for corporate legal services, a unique combination of factors explains the incredible rise of the Jewish firms. First, white-shoe ethos caused large WASP firms to stay out of undignified practice areas and effectively created pockets of Jewish practice areas, where the Jewish firms encountered little competition for their services. Second, hiring and promotion discriminatory practices by the large WASP firms helped create a large pool of talented Jewish lawyers from which the Jewish firms could easily recruit. Finally, the Jewish firms benefited from a flip side of bias phenomenon, that is, they benefited from the positive consequences of stereotyping. Paradoxically, the very success of the Jewish firms is reflected in their demise by the early twenty-first century: because systematic large law firm ethno-religious discrimination against Jewish lawyers has become a thing of the past, the very reason for the existence of Jewish law firms has been nullified. As other minority groups, however, continue to struggle for equality within the senior ranks of Big Law, can the experience of the Jewish firms serve as a “separate-but-equal” blueprint for overcoming contemporary forms of discrimination for women, racial, and other minority attorneys? Perhaps not. As this chapter establishes, the success of large Jewish law firms was the result of unique conditions and circumstances between 1945 and 1980, which are unlikely to be replicated. For example, large law firms have become hyper-competitive and are not likely to allow any newcomers the benefit of protected pockets of practice. While smaller “separate-but-equal” specialized firms, for instance, ones exclusively hiring lawyer-mothers occasionally appear, the rise of large “separate-but-equal” firms is improbable.

Short nomenclator or vocabular in English and Hebrew: composed alphabetically for the use and benefit of my pupils in particular and for the advantage of those who are desirous to obtain the knowledge of the Hebrew tongue in general, which may be that great help to understand not only ye sacred oracles in their original, but even any Jewish author (so far as concern owns) as also it may give great insight in ye tongue to those, as to compose it, a work altogether new, [ca. 1735]

Headed on the first page with the words "Nomenclatura hebraica," this handwritten volume is a vocabulary with the Hebrew word in the left column, and the English translation on the right. While the book is arranged in sections by letter, individual entries do not appear in strict alphabetical order. The small vocabulary varies greatly and includes entries like enigma, excommunication, and martyr, as well as cucumber and maggot. There are translations of the astrological signs at the end of the volume. Poem written at the bottom of the last page in different hand: "Women when good the best of saints/ that bright seraphick lovely/ she, who nothing of an angel/ wants but truth & immortality./ Verse 2: Who silken limbs & charming/ face. Keeps nature warm."

A manual of Scripture history, for use in Jewish schools and families,

Mode of access: Internet.