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ROLE OF HIPPOCAMPAL NEUROGENESIS IN THE PATHOPHYSIOLOGY AND TREATMENT OF DEPRESSION BENJAMIN ADAM SAMUELS, INDIRA DAVID, QUENTIN RAINER, ALAIN MICHEL GARDIER, RENÉ HEN, DENIS JOSEPH DAVID * Faculty of Pharmacy, University Paris South IV, Paris, France Abstract: Depression and anxiety are psychiatric illnesses that are major burdens on society DQG DIIHFW DV PXFK DV RI WKH ZRUOG¶V SRSXODWLRQ +HUH ZH UHYLHZ FRPPRQ DSSURDFKHV XVHG WR PRGHO GHSUHVVLRQ LQ URGHQWV VXFK DV FKURQLF PLOG VWUHVV &06 VRFLDO GHIHDW DQG chronic corticosterone treatment. We discuss the pros and cons of these different approaches. Furthermore, we provide a detailed review of adult hippocampal neurogenesis, including the distinct phases that a cell passes through when transitioning from precursor to neuron. Finally, we discuss at length the experiments that have related adult hippocampal neurogenesis to treatments of depression and anxiety, and why neurogenesis might be necessary for these treatments. We end by revisiting the neurogenesis hypothesis of depression and by providing suggestions for future research directions. Keywords: 6XEYHQWULFXODU 69= DQG VXEJUDQXODU ]RQH 6*= RI GHQWDWH J\UXV '* RI KLSSRFDPSXV doublecortin (DCX) expressing cells, adult neurogenesis, cell differentiation, depression, antidepressant drugs, animal models. 1. INTRODUCTION 'HSUHVVLYH DQG DQ[LHW\ GLVRUGHUV DUH D PDMRU EXUGHQ RQ VRFLHW\ 0RRG GLVRUGHUV DIIHFW RI WKH ZRUOG¶V SRSXODWLRQ ZKLOH VHYHUH IRUPV RI GHSUHVVLRQ LPSDFW RI WKH 86 SRSXODWLRQ > @ )XUWKHUPRUH DSSUR[LPDWHO\ PLOOLRQ DGXOWV LQ WKH 86 SRSXODWLRQ >@ H[SHULHQFH DQ HSLVRGH RI PDMRU GHSUHVVLRQ LQ WKHLU OLIHWLPH >@ 7KH KHWHURJHQHRXV QDWXUH RI GHSUHVVLRQ VXJJHVWV DQ involvement of multiple distinct brain regions, which may be responsible for the diverse symptoms. Human imaging and post-mortem studies have supported this hypothesis, implicating brain areas including the prefrontal and cingulate cortex, hippocampus, striatum, amygdala, and thalamus >@ 7RJHWKHU WKHVH EUDLQ UHJLRQV RSHUDWH D VHULHV RI KLJKO\ LQWHUDFWLQJ FLUFXLWV WKDW IRUPV D QHXUDO FLUFXLWU\ LQYROYHG LQ GHSUHVVLRQ >@. The hippocampus is one of several limbic structures that have been extensively studied in individuals with psychiatric and neurologic disorders in the last decade > @ %HVLGHV LWV FULWLFDO UROH LQ OHDUQLQJ DQG PHPRU\ WKH KLSSRFDPSXV LV RQH RI RQO\ WZR DUHDV LQ PDPPDOLDQ EUDLQ ZKHUH DGXOW QHXURJHQHVLV RFFXUV >@ $GXOW KLSSRFDPSDO QHXURJHQHVLV LV WKHUHIRUH GH¿QHG DV WKH SURJUHVVLRQ IURP QHXUDO VWHP FHOO WR PDWXUH GHQWDWH JUDQXOH QHXURQ 0RUHRYHU ZKLOH PDQ\ FODVVHV RI GUXJV ZLWK DQWLGHSUHVVDQW DFWLYLW\ KDYH EHHQ GHYHORSHG DQG DSSURYHG >@ PDQ\ SDWLHQWV GR QRW UHVSRQG WR WUHDWPHQW >@ 7KHUHIRUH LW LV FULWLFDO IRU EDVLF UHVHDUFK to develop animal models that present behavioral, neurochemical and brain morphological phenotypes UHPLQLVFHQW RI GHSUHVVLRQ DQG DQ[LHW\ *LYHQ WKDW DQ[LHW\ DQG GHSUHVVLRQ KDYH D KLJK FRPRUELGLW\ * Address correspondence to Denis J. David: )DFXOW\ RI 3KDUPDF\ 8QLYHUVLW\ 3DULV 6RXWK ,9 3DULV )UDQFH E-mail: denis. [email protected] Bruno P Guiard and Eliyahu Dremencov (Eds) All rights reserved - © 2013 Bentham Science Publishers 210 Neurobiology of Mood Disorders, 2013, 210-233 CHAPTER 9 Send Orders for Reprints to [email protected]
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Page 1: role of hippocampal neurogenesis in the pathophysiology and ...

ROLE OF HIPPOCAMPAL NEUROGENESIS IN THE PATHOPHYSIOLOGY AND TREATMENT

OF DEPRESSION

BENJAMIN ADAM SAMUELS, INDIRA DAVID, QUENTIN RAINER, ALAIN MICHEL GARDIER, RENÉ HEN, DENIS JOSEPH DAVID*

Faculty of Pharmacy, University Paris South IV, Paris, France

Abstract: Depression and anxiety are psychiatric illnesses that are major burdens on society DQG� DIIHFW� DV� PXFK� DV� ��� RI� WKH� ZRUOG¶V� SRSXODWLRQ�� +HUH� ZH� UHYLHZ� FRPPRQ� DSSURDFKHV�XVHG� WR� PRGHO� GHSUHVVLRQ� LQ� URGHQWV� VXFK� DV� FKURQLF� PLOG� VWUHVV� �&06��� VRFLDO� GHIHDW�� DQG�chronic corticosterone treatment. We discuss the pros and cons of these different approaches. Furthermore, we provide a detailed review of adult hippocampal neurogenesis, including the distinct phases that a cell passes through when transitioning from precursor to neuron. Finally, we discuss at length the experiments that have related adult hippocampal neurogenesis to treatments of depression and anxiety, and why neurogenesis might be necessary for these treatments. We end by revisiting the neurogenesis hypothesis of depression and by providing suggestions for future research directions.

Keywords:�6XEYHQWULFXODU��69=��DQG�VXEJUDQXODU�]RQH��6*=��RI�GHQWDWH�J\UXV��'*��RI�KLSSRFDPSXV��doublecortin (DCX) expressing cells, adult neurogenesis, cell differentiation, depression, antidepressant drugs, animal models.

1. INTRODUCTION

'HSUHVVLYH� DQG� DQ[LHW\� GLVRUGHUV� DUH� D� PDMRU� EXUGHQ� RQ� VRFLHW\�� 0RRG� GLVRUGHUV� DIIHFW� ��� RI�WKH�ZRUOG¶V� SRSXODWLRQ��ZKLOH� VHYHUH� IRUPV� RI� GHSUHVVLRQ� LPSDFW� ����� RI� WKH�86� SRSXODWLRQ� >����@�� )XUWKHUPRUH�� DSSUR[LPDWHO\� ������ PLOOLRQ� DGXOWV� LQ� WKH� 86� SRSXODWLRQ� >���@� H[SHULHQFH� DQ�HSLVRGH�RI�PDMRU�GHSUHVVLRQ�LQ�WKHLU�OLIHWLPH�>�@��7KH�KHWHURJHQHRXV�QDWXUH�RI�GHSUHVVLRQ�VXJJHVWV�DQ�involvement of multiple distinct brain regions, which may be responsible for the diverse symptoms. Human imaging and post-mortem studies have supported this hypothesis, implicating brain areas including the prefrontal and cingulate cortex, hippocampus, striatum, amygdala, and thalamus >�@��7RJHWKHU��WKHVH�EUDLQ�UHJLRQV�RSHUDWH�D�VHULHV�RI�KLJKO\�LQWHUDFWLQJ�FLUFXLWV�WKDW�IRUPV�D�QHXUDO�FLUFXLWU\�LQYROYHG�LQ�GHSUHVVLRQ�>�@. The hippocampus is one of several limbic structures that have been extensively studied in individuals with psychiatric and neurologic disorders in the last decade >����@��%HVLGHV�LWV�FULWLFDO�UROH�LQ�OHDUQLQJ�DQG�PHPRU\��WKH�KLSSRFDPSXV�LV�RQH�RI�RQO\�WZR�DUHDV�LQ�PDPPDOLDQ�EUDLQ�ZKHUH�DGXOW�QHXURJHQHVLV�RFFXUV�>�@��$GXOW�KLSSRFDPSDO�QHXURJHQHVLV�LV�WKHUHIRUH�GH¿QHG�DV�WKH�SURJUHVVLRQ�IURP�QHXUDO�VWHP�FHOO�WR�PDWXUH�GHQWDWH�JUDQXOH�QHXURQ��

0RUHRYHU�� ZKLOH� PDQ\� FODVVHV� RI� GUXJV� ZLWK� DQWLGHSUHVVDQW� DFWLYLW\� KDYH� EHHQ� GHYHORSHG� DQG�DSSURYHG�>�@��PDQ\�SDWLHQWV�GR�QRW�UHVSRQG�WR�WUHDWPHQW�>�@��7KHUHIRUH�LW�LV�FULWLFDO�IRU�EDVLF�UHVHDUFK�to develop animal models that present behavioral, neurochemical and brain morphological phenotypes UHPLQLVFHQW�RI�GHSUHVVLRQ�DQG�DQ[LHW\��*LYHQ�WKDW�DQ[LHW\�DQG�GHSUHVVLRQ�KDYH�D�KLJK�FRPRUELGLW\�*Address correspondence to Denis J. David: )DFXOW\�RI�3KDUPDF\��8QLYHUVLW\�3DULV�6RXWK�,9��3DULV��)UDQFH��E-mail: [email protected]

Bruno P Guiard and Eliyahu Dremencov (Eds) All rights reserved - © 2013 Bentham Science Publishers

210 Neurobiology of Mood Disorders, 2013, 210-233

CHAPTER 9

Send Orders for Reprints to [email protected]

Page 2: role of hippocampal neurogenesis in the pathophysiology and ...

ZLWK� FR�RFFXUUHQFH� UDWHV� XS� WR� ���� LQ�SDWLHQWV� >��� ��@�� DQLPDO�PRGHOV� WKDW� SUHVHQW� VLJQV� RI� ERWK�diseases could potentially be the most useful.

To fully understand the pathophysiology and treatment of depression, it is essential to delineate molecular, cellular and circuit-level determinants of chronic antidepressant action in addition WR�EHKDYLRUDO�PRGHOV��2I� WKH�FXUUHQW� OHDGLQJ�K\SRWKHVHV�RI� WKH�SDWKRSK\VLRORJ\�DQG� WUHDWPHQW�RI�depression, the Neurogenesis Hypothesis of Depression deserves particular attention because it allows the characterization because changes in neurogenesis are only seen after chronic, but not acute, antidepressant treatment. This review revisits the role of adult hippocampal neurogenesis in the pathophysiology of mood disorders, especially anxiety/depression, and also in the antidepressant responses, especially in non-stressed and stressed rodents.

2. HIPPOCAMPAL NEUROGENESIS

1HXURJHQHVLV�UHIHUV�WR�WKH�SURGXFWLRQ�RI�QHZ�QHXURQV�LQ�WKH�EUDLQ��2ULJLQDOO\��LW�ZDV�RQO\�GHVFULEHG�GXULQJ�GHYHORSPHQW��7KH�GRJPD�RI�5DPRQ�\�&DMDO��������WKDW�WKH�DGXOW�EUDLQ�ZDV�XQDEOH�RI�JHQHUDWLQJ�QHZ�QHXURQV�ZDV�¿UVW�TXHVWLRQHG�E\�WKH�ZRUN�RI�$OWPDQ�LQ�WKH�����V��ZKR�UHYHDOHG�WKH�JHQHVLV�RI�QHZ�FHOOV�LQ�WKH�EUDLQ�RI�DGXOW�UDW�DQG�FDW�E\�DXWRUDGLRJUDSK\�ZLWK�WULWLDWHG�WK\PLGLQH�>��@��8QIRUWXQDWHO\��LW�ZDV�XQFHUWDLQ�ZKHWKHU�WKH�QHZ�FHOOV�ZHUH�DFWXDOO\�QHXURQDO�FHOOV��7KH�ZRUN�RI�.DSODQ�DQG�+LQGV��������>��@�FRQ¿UPHG�WKLV�E\�XVLQJ�DQ�XOWUDVWUXFWXUDO�DQDO\VLV�RI�WKH�ODEHOHG�FHOOV��0DQ\�\HDUV�ODWHU��D�FRPELQDWLRQ�RI�VSHFL¿F�QHXURQDO�PDUNHUV�DQG�DQ�DQDORJXH�RI�WK\PLQLGLQH����EURPR��¶�GHR[\�XULGLQH��%UG8���FRQ¿UPHG�WKH�QHXURQDO�SKHQRW\SH�>��@��7KH�SURFHVV�RI�DGXOW�QHXURJHQHVLV�LV�ORFDWHG�LQ�WZR�GLVFUHWH�EUDLQ�UHJLRQV��WKH�VXEYHQWULFXODU�]RQH��69=��DQG�VXEJUDQXODU�]RQH��6*=��RI�GHQWDWH�J\UXV�RI�WKH�KLSSRFDPSXV��,Q�WKLV�chapter, only the hippocampal neurogenesis and its involvement in depression will be presented.

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+LSSRFDPSDO�QHXURJHQHVLV�LV�SRVVLEOH�LQ�WKH�6*=�RI�WKH�GHQWDWH�J\UXV�RI�WKH�KLSSRFDPSXV�EHFDXVH�of to the presence of stem cells. These stem cells evolve into neural progenitor cells that can produce multiple cell types in the central nervous system such as neurons, astrocytes, oligodendrocytes, RU�PLFURJOLDO� FHOOV� >��@�� ,Q� URGHQWV�� WKH� GXUDWLRQ� RI� WKH�PLWRWLF� F\FOH� RI� SUROLIHUDWLQJ� SUHFXUVRUV�LV�DSSUR[LPDWHO\����WR����KRXUV��OHDGLQJ�WR�WKH�SURGXFWLRQ�RI�DERXW�������WR��������QHZ�QHXURQV�SHU� GD\� >��@� *LYHQ� WKDW� WKH� GHQWDWH� J\UXV� FRQVLVWV� RI� DSSUR[LPDWHO\� RQH� PLOOLRQ� JUDQXOH� FHOOV��WKLV� SKHQRPHQRQ� LV� FDSDEOH� RI� JHQHUDWLQJ� D� OLWWOH� OHVV� WKDQ� ��� RI� WRWDO� JUDQXOH� FHOOV� HDFK� GD\��+RZHYHU�� WKH� SURSRUWLRQ� RI� QHZ� QHXURQV� WKDW� VXUYLYH� EH\RQG� RQH�PRQWK� LV� OHVV� WKDQ� ����� DQG�the production of new cells is offset by the daily loss of mature granule cells. The surviving cells DUH�SUHGRPLQDQWO\�D�QHXURQDO�SKHQRW\SH��������PDLQO\�JOXWDPDWHUJLF�JUDQXOH�FHOOV��EXW�DOVR�VRPH�DUH�*$%$HUJLF�LQWHUQHXURQ�EDVNHW�FHOOV��$�VPDOOHU�SURSRUWLRQ�RI�FHOOV�GLIIHUHQWLDWH�LQWR�DVWURF\WHV��������ROLJRGHQGURF\WHV�RU�PLFURJOLD�>��@�

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Adult hippocampal neurogenesis, therefore, mainly refers to the production of a single neuronal type: the granule cells of the dentate gyrus. These cells are the principal excitatory neurons of the dentate J\UXV��'*���UHFHLYLQJ�FRQQHFWLRQV�IURP�WKH�HQWRUKLQDO�FRUWH[�DQG�VHQGLQJ�SURMHFWLRQV�DORQJ�PRVV\�¿EHUV�LQWR�WKH�&$��VXE¿HOG�RI�WKH�KLSSRFDPSXV��ZKHUH�WKH\�WHUPLQDWH�LQ�VWUXFWXUHV�ULFK�LQ�V\QDSVHV�and interneurons. Several projections are also sent into the hilus. The precursors are located between WKH�KLOXV�DQG�WKH�JUDQXODU�]RQH��LQ�D�QLFKH�FDOOHG�WKH�VXEJUDQXODU�]RQH��6*=���7KH�6*=�SURYLGHV�D�

Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression Neurobiology of Mood Disorders 211

Page 3: role of hippocampal neurogenesis in the pathophysiology and ...

microenvironment that promotes neuronal development. This neurogenic niche includes precursors, immature neurons, glial and endothelial cells, microglia and some immune cells. The niche is surrounded by a basement membrane. Because of the important role of vascularization in this region, WKLV�QLFKH�LV�DOVR�FDOOHG�D�YDVFXODU�QLFKH�>��@��,Q�DOO�FDVHV��WKH�QLFKH�SURYLGHV�D�XQLTXH�HQYLURQPHQW�IRU�neuronal development. Studies suggest that astrocytes have a local key role in neurogenesis. In vivo, the development of cells has a preferred spatial relationship with astrocytes. Ex vivo, astrocytes and DVWURF\WH�GHULYHG�IDFWRUV�DUH�SRWHQW�LQGXFHUV�RI�KLSSRFDPSDO�QHXURJHQHVLV�IRU�WKH�SUHFXUVRUV�>��@��7KH�6*=�LV�DOVR�VSHFLDO�EHFDXVH�LW�UHFHLYHV�FRQQHFWLRQV�IURP�VHYHUDO�EUDLQ�UHJLRQV��GRSDPLQH�¿EHUV�LQ�WKH�ventral tegmental area, projections of serotonergic raphe nuclei, septum acetylcholine connections, DQG�FRQQHFWLRQV�RI�*$%$HUJLF�ORFDO�LQWHUQHXURQV��0DQLSXODWLRQV�RI�WKHVH�QHXURWUDQVPLWWHU�V\VWHPV�KDV�DOVR�GHPRQVWUDWHG�UHJXODWRU\�HIIHFWV�RQ�QHXURJHQHVLV�>��@�>��@��7KH�IDFW�WKDW�WKHVH�QHXURWUDQVPLWWHU�systems regulate neurogenesis is of particular interest because antidepressants mainly act by changing PRQRDPLQH�OHYHOV�>VHH�ODWHU�VHFWLRQ�HQWLWOHG�$17,'(35(66$176�$1'�$'8/7�+,332&$03$/�1(852*(1(6,6@��$�SURPLQHQW�H[DPSOH�LV�WKDW�PLFH�GH¿FLHQW�LQ�WKH�6HURWRQLQ��$�UHFHSWRU�GR�QRW�VKRZ�D�QHXURJHQLF�UHVSRQVH�WR�FKURQLF�ÀXR[HWLQH�WUHDWPHQW�>��@�

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Neurogenesis can be divided into four phases: a step in which precursor cells are dividing, then surviving, a post mitotic maturation phase, and a late phase of survival.

2.3.1. The stage of precursor cellThe precursors have properties reminiscent of glial cells, including the morphology of radial glia. The cell body is located in the subgranular zone and the dendrites extend into the molecular layer. The QDWXUH�RI�KLSSRFDPSDO�DVWURF\WH�SUHFXUVRUV�ZDV�¿UVW�UHYHDOHG�E\�>��@��7\SH���SUHFXUVRU�FHOOV�\LHOG�intermediate progenitor cells, or type-2 cells, with a high proliferation activity. A subset of these cells continue to express glial markers, but lack the morphological characteristics of radial cells (type-�D���7KH�W\SH���FHOOV�WKDW�H[SUHVV�QHVWLQ�¿ODPHQWV��VXFK�DV�FHOO�W\SH����DOVR�H[SUHVV�PDUNHUV�VXFK�DV�1(852'��DQG�3UR[���7KLV�SDUWLFXODU�SKHQRW\SH�LV�XVHG�WR�FODVVLI\�FHOOV�DV�W\SH��E�>������@��3UR[��LV�VSHFL¿F�WR�WKH�GHYHORSPHQW�RI�JUDQXOH�FHOOV��,Q�W\SH���FHOOV��WKH�GHYHORSLQJ�FHOOV�UHFHLYH�*$%$HUJLF�LQQHUYDWLRQ�>��@��DQG�DUH�PRUH�VHQVLWLYH�WR�*$%$HUJLF�VWLPXODWLRQ��6LPLODUO\��W\SH���FHOOV�UHVSRQG�WR�WKHVH�VWLPXOL�E\�LQFUHDVLQJ�FHOO�SUROLIHUDWLRQ�>��@��$PRQJ�WKH�HDUO\�H[SUHVVHG�QHXURQDO�PDUNHUV��doublecortin (DCX) is expressed on the type-2b cells. The expression of DCX extends from the SUROLIHUDWLRQ�SKDVH�WR�SRVW�PLWRWLF�PDWXUDWLRQ��ZKLFK�ODVWV�DERXW�����ZHHNV�>��@�

2.3.2. The phase of survival6RRQ�DIWHU�WKH�UHOHDVH�RI�WKH�FHOO�F\FOH��QHZ�QHXURQV�H[SUHVV�PDUNHUV��VXFK�1HX1�>³6SHFL¿F�QHXURQDO�QXFOHDU� SURWHLQ´@� DQG� WKH� WUDQVLHQW� PDUNHU� FDOUHWLQLQ� >��@�� $� PDMRULW\� RI� FHOOV� IDLO� WR� HVWDEOLVK�connections with the molecular layer and die. In contrast, cells that establish stable connections GHYHORS�D�VWDEOH�GHQGULWLF�DUERUL]DWLRQ�WKDW�H[WHQGV�LQ�D�VSHFL¿F�ZD\�LQ�WLPH��,Q�WKH�GD\V�IROORZLQJ�the exit of the cell cycle, new cells emanate their axons to their target region CA3 to form appropriate V\QDSVHV��7KLV�SHULRG�LV�PDUNHG�E\�WKH�H[SUHVVLRQ�RI�D�SURWHLQ�PHGLDWRU��VXFK�DV�72$'����RU�78&����LPSOLFDWHG�LQ�D[RQ�JXLGDQFH��7KH�¿UVW�*$%$HUJLF�LQQHUYDWLRQV�DUH�H[FLWDWRU\�DQG�WKHQ�EHFRPH�LQKLELWRU\�ZKHQ�JOXWDPDWHUJLF�FRQQHFWLRQV�DUH�HVWDEOLVKHG�>��@��7KH�*$%$HUJLF�DFWLRQ�OHDGV�FHOOV�WR�PDWXUH�LQWR�JOXWDPDWHUJLF�FHOOV�DQG�WR�GHYHORS�V\QDSWLF�LQWHJUDWLRQ�>��@�0RVW�UHJXODWRU\�HOHPHQWV�DQG�SURFHVVHV�RFFXU�DW�WKH�VWDJH�RI�QHXURQDO�GHYHORSPHQW��DQG�UDUHO\�GXULQJ�WKH�H[SDQVLRQ�SKDVH�>������@�

2.3.3. The maturation step; from early to late stage'RXEOHFRUWLQ�LV�H[SUHVVHG�LQ�JUDQXOH�FHOOV�WKDW�UDQJH�IURP���GD\�WR�DERXW���ZHHNV�RI�DJH��ZLWK�����RI� LWV� WRWDO� SRSXODWLRQ� EHLQJ� SUROLIHUDWLQJ� QHXUREODVWV� DQG� WKH� UHVW� EHLQJ� SRVW�PLWRWLF� QHXURQV� >��@��

212 Neurobiology of Mood Disorders Samuels et al.

Page 4: role of hippocampal neurogenesis in the pathophysiology and ...

$QRWKHU�PDUNHU�RI�PDWXUDWLRQ��FDOOHG�FDOUHWLQLQ��LV�DOVR�XVHG�DV�D�PDUNHU�IRU�LPPDWXUH�*&V�DW�WKH�HDUO\�postmitotic stage. The period of expression of calretinin (3-4 weeks), is closely linked to dendritic PDWXUDWLRQ��+RZHYHU��XVLQJ�D�OHQWLYLUDO�DSSURDFK�H[SUHVVLQJ�WKH�*UHHQ�)OXRUHVFHQW�SURWHLQ��LW�KDV�EHHQ�VKRZQ�WKDW�WKH�D[RQDO�JURZWK�WR�&$��SUHFHGHV�WKH�GHYHORSPHQW�RI�GHQGULWLF�DUERUL]DWLRQ�>��@��$IWHU�full integration to existing circuits, the new cells move from the calcium-binding protein calretinin to FDOELQGLQ�>��@��,W�LV�VHYHUDO�ZHHNV�EHIRUH�WKH�FHOOV�DUH�QR�ORQJHU�GLVWLQJXLVKDEOH�HOHFWURSK\VLRORJLFDOO\�IURP�PDWXUH�QHXURQV�RI�WKH�JUDQXOH�FHOOV�>��@��,W�KDV�EHHQ�SRVWXODWHG�WKDW�WKH�WLPH�QHHGHG�WR�FRPSOHWH�WKH�functionality of these young neurons is related to the formation and storage of new elements of memory >��@��)LQDOO\��FDOELQGLQ�OLNH�LPPXQRUHDFWLYLW\�KDV�EHHQ�GHVFULEHG�DV�D�PDUNHU�IRU�PDWXUH�JUDQXOH�FHOOV�

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For a full characterization of the neurogenic effects of new compounds, all the steps of neurogenesis, including proliferation, survival, maturation, and differentiation have to be completed. So far, QR� VSHFL¿F� DQG� H[FOXVLYH�PDUNHU� KDV� EHHQ� LGHQWL¿HG� WKDW�ZRXOG� DOORZ� IRU� SURVSHFWLYH� VWXGLHV� RI�neurogenesis. As a result, detection of neurogenic steps depends on a combination of labeling DSSURDFKHV��7KXV�� SUROLIHUDWLRQ��GLIIHUHQWLDWLRQ� DQG� VXUYLYDO� VWHSV� HDFK� UHTXLUH� D� VSHFL¿F�SURWRFRO�XVLQJ� WKH� DGPLQLVWUDWLRQ� RI� D� V\QWKHWLF� WK\PLGLQH� DQDORJXH�� ³��EURPR��¶�GHR[\XULGLQH´� �%UG8��that substitutes for thymidine incorporation into DNA synthesized during the S phase of the cycle. 4XDQWLWDWLYH� DQDO\VLV� RI� SUROLIHUDWLRQ�� GLIIHUHQWLDWLRQ�� DQG� VXUYLYDO� RI� QHZERUQ� FHOOV� LV� PDGH� E\�YDU\LQJ�WKH�WLPH�LQWHUYDO�EHWZHHQ�WKH�SXOVH�DGPLQLVWUDWLRQ�RI�%UG8�DQG�WKH�VDFUL¿FH�RI�DQLPDOV�>��@��

2.4.1. Main methods for a Detection of cell proliferation)RU� WKH�TXDQWL¿FDWLRQ�RI� UDWH�RI�FHOO�GLYLVLRQ��DQLPDOV�DUH�DGPLQLVWHUHG�%UG8�>EHWZHHQ���� WR�����PJ�NJ� �K� EHIRUH� VDFUL¿FH� >��@�� 3UROLIHUDWLRQ� LV� TXDQWL¿HG� E\� FRXQWLQJ� %UG8�SRVLWLYH� FHOOV�� 7R�VLPSOLI\�WKH�H[SHULPHQW��TXDQWL¿FDWLRQ�RI�%UG8�SRVLWLYH�FOXVWHUV�FDQ�DOVR�EH�SHUIRUPHG�WR�PHDVXUH�proliferation since a positive correlation exists between BrdU-positive clusters and BrdU-positive FHOOV��6LQFH�WKH�TXDQWL¿FDWLRQ�RI�%UG8�SRVLWLYH�FOXVWHUV�LV�PXFK�OHVV�WLPH�FRQVXPLQJ�WKDQ�FRXQWLQJ�BrdU-positive cells, this method can be used as a rapid indicator of the neurogenic effect of drugs RU�RWKHU�PDQLSXODWLRQV�>��@��7KLV�LV�LPSRUWDQW�DOVR�EHFDXVH�%UG8�LPPXQRVWDLQLQJ�KDV�EHHQ�XVHG�QRW�only to test whether new drugs affect adult hippocampal neurogenesis, but also whether the anxiety/depressive-like state has been related to changes in hippocampal neurogenesis.

2.4.2. Endogenous markers of cell proliferationEndogenous cell cycle proteins are expressed at different stages of cell cycle progression. For exemple the “Proliferating Cell Nuclear Antigen, PCNA” is expressed throughout the cell cycle and provide ORZ�WHPSRUDO�UHVROXWLRQ��.L����FORVHO\�FRUUHVSRQGV�WR�%UG8�DV�LW�LV�H[SUHVVHG�ERWK�GXULQJ�6�SKDVH�DQG�through the remainder of the cell cycle (Figure 1).

2.4.3. Survival and fate of the newly generated cells8VXDOO\��IRU�WKH�TXDQWL¿FDWLRQ�RI�UDWH�RI�FHOO�VXUYLYDO��DQLPDOV�DUH�DGPLQLVWHUHG�%UG8������WR�����PJ�NJ��WZLFH�D�GD\�GXULQJ�WKUHH�GD\V����WR���ZHHNV�EHIRUH�VDFUL¿FH�>��@��7KH�UHDVRQ�WR�ZDLW�IRU�VDFUL¿FH�LV�that the fate of the newly generated cells can only be determined three to four weeks later, once neuronal PLJUDWLRQ�KDV�RFFXUUHG�>������@��2QFH�SURJHQLWRU�FHOOV�UHDFK�PDWXULW\�WKH\�EHJLQ�H[SUHVVLQJ�QHXURQDO�PDUNHUV�VXFK�DV�QHXUR¿ODPHQWV��1HX1��DQG�&DOFLXP�ELQGLQJ�SURWHLQV�RU�DVWURF\WH�PDUNHUV�VXFK�DV�JOLDO�¿EULOODU\�DFLGLF�SURWHLQ��*)$3���&DOFLXP�ELQGLQJ�SURWHLQV�VXFK�DV�FDOELQGLQ�DUH�SURGXFHG�ZKHQ�FHOOV�become electrophysiological active. It is not until 4 weeks after birth that newly generated granule cells KDYH�DFTXLUHG�WKH�W\SLFDO�IHDWXUHV�RI�PDWXUH�JUDQXOH�FHOOV�DQG�FHDVH�WR�H[SUHVV�LPPDWXUH�QHXURQDO�PDUNHUV�

Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression Neurobiology of Mood Disorders 213

Page 5: role of hippocampal neurogenesis in the pathophysiology and ...

2.4.4. Markers of maturationSeveral markers have been used to assess maturation such as microtubule-associated protein >GRXEOHFRUWLQ@��,Q�WKH�DGXOW�GHQWDWH�J\UXV��'&;�LV�H[FOXVLYHO\�H[SUHVVHG�LQ�LPPDWXUH�QHXURQV�>������@��DQG�WKXV�KDV�EHHQ�ZLGHO\�XVHG�DV�DQ�LPPDWXUH�QHXURQDO�PDUNHU�WKDW�UHOLDEO\�UHÀHFWV�WKH�OHYHO�RI�QHXURJHQHVLV�DQG�LWV�PRGXODWLRQ�>��@��7R�DVVHVV�WKH�LPSDFW�RI�DQWLGHSUHVVDQWV�RQ�GHQGULWLF�PDWXUDWLRQ��the morphology of cells that express doublecortin (DCX) are examined. DCX-positive cells with tertiary dendrites, which display more complex dendritic arborization, can be distinguished from others DCX cells. The ratio of DCX-positive cells with tertiary dendrites over total DCX-positive cells is informative of the rate of maturation. The polysialylated form of the neural cell adhesion molecule �36$�1&$0��DOVR�KDV�D�WUDQVLHQW�H[SUHVVLRQ�SDWWHUQ�WKDW�PDUNV�QHXURQDO�SURJHQLWRUV��+RZHYHU��LW�VKRXOG�EH�QRWHG�WKDW��LQ�FRQWUDU\�WR�'&;��36$�1&$0�KDV�DOVR�EHHQ�GHWHFWHG�LQ�JOLDO�FHOOV�

�����0(7+2'6�86('�72�$%/$7(�25�,1&5($6(�1(852*(1(6,6

The analysis of the causal relationship between neurogenesis and behavior came from the removal of progenitor cells. Several methods to date have been developed to reduce or abolish neurogenesis (Table 1):

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,Q�D�FRQWUDU\�H[SHULPHQW��6DKD\�DQG�FROOHDJXHV�>��@�GHYHORSHG�D�JHQHWLF�JDLQ�RI�IXQFWLRQ�VWUDWHJ\�WR�LQGXFLEO\�DXJPHQW�WKH�VXUYLYDO�RI�DGXOW�ERUQ�QHXURQV�LQ�D�FHOO�DXWRQRPRXV�PDQQHU�>��@��%HFDXVH�

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Figure 1: Schema representing the endogenous or exogenous markers used to study adult neurogenesis

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214 Neurobiology of Mood Disorders Samuels et al.

Page 6: role of hippocampal neurogenesis in the pathophysiology and ...

��±����RI�\RXQJ�DGXOW�ERUQ�QHXURQV�XQGHUJR�SURJUDPPHG�FHOO�GHDWK��IRU�ZKLFK�WKH�SUR�DSRSWRWLF�JHQH�%D[�LV�UHTXLUHG��WKH\�XVHG�D�WUDQVJHQLF�PRXVH�OLQH�LQ�ZKLFK�WKH�WDPR[LIHQ��7$0��UHJXODWDEOH�UHFRPELQDVH�&UH(57��LV�H[SUHVVHG�XQGHU�WKH�FRQWURO�RI�D������NLOREDVH�IUDJPHQW�RI�WKH�UDW�QHVWLQ��1HV��JHQH�SURPRWHU�>��@�WRJHWKHU�ZLWK�D�ÀR[HG�%D[�PRXVH�OLQH�WR�DEODWH�%D[�VHOHFWLYHO\�LQ�QHXUDO�stem cells in the adult brain and promote survival.

3. HIPPOCAMPAL NEUROGENESIS AND MAJOR DEPRESSION AND ITS TREATMENT

�����7+(�$1;,(7<���'(35(66,21�67$7(�$1'�+,332&$03$/�1(852*(1(6,6

The neurogenic hypothesis of depression postulates that decreased production of new granule cells in the dentate gyrus of the hippocampus is linked to the pathophysiology of depression and that WKH� LQFUHDVH� LQ� KLSSRFDPSDO� QHXURJHQHVLV� LV� UHTXLUHG� IRU� WKH� EHKDYLRUDO� HIIHFWV� RI� DQWLGHSUHVVDQW�WUHDWPHQW�>��@��7KH�IHZ�VWXGLHV�RI�KLSSRFDPSDO�QHXURJHQHVLV�LQ�GHSUHVVHG�SDWLHQWV�SXEOLVKHG�WR�GDWH�have mainly relied on histological examinations of post-mortem brain tissue and studies of magnetic resonance imaging. Thus, a reduction in hippocampal volume in depressed patients is somewhat HVWDEOLVKHG�� DQG� WKH� FRQWULEXWLRQ� RI� WZR� PHWD�DQDO\VLV� FRQ¿UPHG� WKLV� UHGXFWLRQ� LQ� KLSSRFDPSDO�YROXPH�LQ�SDWLHQWV�ZLWK�GHSUHVVLRQ�>��@��7KH�IUHTXHQF\�RI�GHSUHVVLYH�HSLVRGHV�DQG�WKH�SHULRG�GXULQJ�which they are not treated coincide with the severity of the decline in hippocampal volume. However, pathophysiological studies on post-mortem brain tissue indicates that the change in the number of QHXURSLO�DQG�JOLDO�FHOOV�PD\�EH�UHVSRQVLEOH�IRU�UHGXFLQJ�WKH�YROXPH�RI�WKH�KLSSRFDPSXV�>��@��,W�LV�highly unlikely that loss of hippocampal neurogenesis can account for the decreased volume. These imaging results, involving hippocampal neurogenesis in the pathophysiology of major depressive HSLVRGHV��KDYH�EHHQ�FKDOOHQJHG�E\�D�UHFHQW�KLVWRORJ\�VWXG\�>��@��7KLV�VWXG\�GLG�QRW�DFWXDOO\�GHWHFW�WKH�GLIIHUHQFH�LQ�VWHP�FHOO�SUROLIHUDWLRQ�>E\�.L���@�LQ�WKH�KLSSRFDPSXV�EHWZHHQ�SDWLHQWV�ZLWK�GHSUHVVLRQ�and healthy volunteers. The results of this study are limited, however, since the patients were on DQWLGHSUHVVDQW�PHGLFDWLRQ�DW�WKH�WLPH�RI�GHDWK��ZKLFK�FRXOG�PDVN�WKH�VSHFL¿F�HIIHFWV�RI�GHSUHVVLRQ�on cell proliferation. In addition, in the absence of toxicology studies, it is not clear that the patients REVHUYHG� WUHDWPHQW��0RUHRYHU�� JLYHQ� WKH� GLYHUVLW\� LQ� WKH� VWDJHV� RI� QHXURJHQHVLV�� LW� LV� GLI¿FXOW� WR�conclude any involvement of neurogenesis after only observation of cell proliferation. In contrast, D�PRUH� UHFHQW� VWXG\� DFWXDOO\� VKRZHG� D� ����GHFUHDVH� LQ� SUROLIHUDWLRQ� >E\�.L���@� LQ� SDWLHQWV�ZLWK�GHSUHVVLRQ�WKDQ�LQ�FRQWUROV�>��@��>��@��+RZHYHU��WKLV�GLIIHUHQFH�GLG�QRW�UHDFK�VWDWLVWLFDO�VLJQL¿FDQFH�

Preclinical studies are useful to prove causal links between hippocampal neurogenesis and behavior. Using exposure to different types of stress, like chronic stress or social submission, causes a

Table 1: 0HWKRGV�XVHG�WR�DEODWH�RU�LQFUHDVH�QHXURJHQHVLV

Pharmacological manipulation Cranial Irradiation Genetic manipulation

��ÀXRURXUDFLO�>��)X@� �PHWK\OD]R[\PHWKDQRO�>0$0@�

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F\WRVLQH�DUDELQRVLGH�>$UD�&@

X-irradiation, gamma-rays*)$3�7.��1HVWLQ�7.��

Nestin-Bax, TrkBOR[�OR[�&UH�(57� Cyclin D2 transgenic

>��@�>��@�>���@ >�������������������������������@� >�������������������������@�

Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression Neurobiology of Mood Disorders 215

Page 7: role of hippocampal neurogenesis in the pathophysiology and ...

decrease in cell proliferation in the hippocampus. It is important to keep in mind the disadvantages RI� WKHVH�PHWKRGV�� VXFK� DV� QRQ�VSHFL¿F� HIIHFWV� RI� DEODWLRQ� WKDW� FDQ� LQYROYH� VWUXFWXUHV� RWKHU� WKDQ�the hippocampus, and therefore other functions. Dysfunction of hippocampal neurogenesis is only K\SRWKHVL]HG�WR�EH�SDUW�RI�WKH�SDWKRJHQHVLV�RI�PDMRU�GHSUHVVLYH�GLVRUGHUV�>��@��>��@��,Q�UHDOLW\��WKH�VXSSUHVVLRQ�RI�KLSSRFDPSDO�QHXURJHQHVLV�LQ�PLFH�GRHV�QRW�DOWHU�DQ[LHW\�EHKDYLRU�LQ�WKH�RSHQ�¿HOG�RU�WKH�OLJKW�GDUN�SDUDGLJPV��WKH�HOHYDWHG�SOXV�PD]H��RU�QRYHOW\�VXSSUHVVHG�IHHGLQJ�>��@��>��@��>��@��7KXV��the X-irradiation in the hippocampus has no effect in the previously mentioned paradigms, suggesting WKDW� WKH� ORVV�RI�KLSSRFDPSDO�QHXURJHQHVLV� LV�QRW�VXI¿FLHQW� IRU�D�EHKDYLRUDO�SKHQRW\SH�RI�DQ[LHW\�depression, and does not exacerbate those induced by stress. Similarly, ablation of neurogenesis by 0$0��D�SKDUPDFRORJLFDO�DJHQW��LV�QRW�VXI¿FLHQW�WR�LQGXFH�DQ�DQKHGRQLF�EHKDYLRU�LQ�UDWV�>��@��$LUDQ�et al�>��@�H[SORUHG�LQ�PRUH�GHWDLO�WKH�OLQN�EHWZHHQ�GHSUHVVLRQ�DQG�KLSSRFDPSDO�QHXURJHQHVLV��,W�LV�clear from their study that chronic stress in rats is not associated with a decrease in neurogenesis, and WKDW� WKH�UHPRYDO�RI�QHXURJHQHVLV�GRHV�QRW� LQGXFH�D�GHSUHVVLYH�OLNH�EHKDYLRU�>��@��+RZHYHU��RWKHU�VWXGLHV�VXJJHVW�WKDW�WKH�PHFKDQLVPV�DUH�PRUH�FRPSOH[��5HFHQWO\�LW�ZDV�VKRZQ�WKDW�DGXOW�KLSSRFDPSDO�QHXURJHQHVLV�SOD\V�DQ�LPSRUWDQW�UROH�LQ�WKH�UHJXODWLRQ�RI�DIIHFWLYH�VWDWHV�>��@��,QGHHG��WUDQVJHQLF�PLFH�WKDW�RYHUH[SUHVV�WKH�SURWHLQ�%D[�LQ�DSRSWRWLF�SURJHQLWRU�FHOOV�DQG�WKXV�KDYH�D�GH¿FLW�LQ�QHXURJHQHVLV��have an anxiety phenotype. In sum, there is evidence indicating that neurogenesis is not a major factor in the development of depression, but may be necessary for the behavioral effects of antidepressants >�@�

4. ANTIDEPRESSANTS AND ADULT HIPPOCAMPAL NEUROGENESIS

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To study the effects of antidepressants in unstressed animals, the choice of the strain is essential. It VKRXOG�EH�QRWHG�WKDW����6Y(Y�PLFH�H[SUHVV�D�ORZ�EDVDO�OHYHO�RI�SUROLIHUDWLQJ�FHOOV�LQ�WKH�6*=��DQG�therefore are more relevant to study an induced increase in antidepressant treatment in conditions ZLWKRXW� VWUHVV� WKDQ�%$/%� �� F-�RU�&��%O� ����PLFH��ZKLFK�H[SUHVV�D�KLJKHU�FHOO�SUROLIHUDWLRQ� >��@��Instead, the study of the impact of stress on hippocampal neurogenesis is more relevant in these last two strains.

(IIHFWV�RI�DQWLGHSUHVVDQWV�RQ�WKH�SUROLIHUDWLRQ�DQG�FHOO�VXUYLYDO��,Q�DGGLWLRQ�WR�WKH�HIIHFWV�RI�ÀXR[HWLQH�>���PJ�NJ@�LQ�LQFUHDVLQJ�FHOO�SUROLIHUDWLRQ�LQ�����6Y(Y7$F�PLFH�>��@�>7DEOH�2@��LW�DOVR�LQFUHDVHV�WKH�VXUYLYDO�RI�SRVWPLWRWLF�JUDQXOH�FHOOV��7KHVH�HIIHFWV�RI�665,V�RQ�SUROLIHUDWLRQ�DQG�FHOO�VXUYLYDO�ZHUH�DOVR�IRXQG�LQ�UDWV�>������@��,W�LV�LPSRUWDQW�WR�QRWH�WKDW�WKH�QHXURJHQLF�HIIHFWV�RI�DQWLGHSUHVVDQWV�DUH�RQO\�VHHQ�ZLWK�FKURQLF�WUHDWPHQW�>�������������@��,Q�DGGLWLRQ��RWKHU�WUHDWPHQWV�VXFK�DV�WKH�DW\SLFDO�antidepressant tianeptine, electroconvulsive therapy, mood stabilizers such as lithium, and new antidepressants such as agomelatine, increase proliferation and cell survival in the adult hippocampus >��@��)XUWKHUPRUH��DJRPHODWLQH�VHOHFWLYHO\�DOWHUV�QHXURJHQHVLV�LQ�WKH�YHQWUDO�KLSSRFDPSXV��D�UHJLRQ�PRUH� LQYROYHG� LQ� WKH� HPRWLRQDO� UHVSRQVH� >��@��7KHUHIRUH�� LW� VHHPV� WKDW� SUROLIHUDWLRQ� DQG� VXUYLYDO�are regulated by distinct mechanisms. For example, an enriched environment increases the survival RI�LPPDWXUH�FHOOV�ZLWKRXW�DIIHFWLQJ�SUROLIHUDWLRQ�>��@��,Q�FRQWUDVW��YROXQWDU\�H[HUFLVH�LQFUHDVHV�WKH�SUROLIHUDWLRQ�DQG�VXUYLYDO��ZLWKRXW�DIIHFWLQJ�WKH�PDWXUDWLRQ�>��@�RU�GHQGULWLF�PRUSKRORJ\�RI�QHZERUQ�QHXURQV�>��@��)LQDOO\��D�UHFHQW�VWXG\�VKRZHG�WKDW�ÀXR[HWLQH�WDUJHWV�D�FODVV�RI�QHXUDO�SURJHQLWRU�FHOOV�E\�GLUHFWO\�LQFUHDVLQJ�V\PPHWULF�GLYLVLRQV�>��@��(IIHFWV�RI�DQWLGHSUHVVDQWV�RQ�WKH�PDWXUDWLRQ��8QWLO�UHFHQWO\�� LW�ZDV�QRW�FOHDU� WKDW�665,V�DOVR� WDUJHWHG� LPPDWXUH�QHXURQV�E\�DIIHFWLQJ� WKHLU�PDWXUDWLRQ�DQG� IXQFWLRQDO� LQWHJUDWLRQ� WR� WKH�QHWZRUN��:DQJ�DQG�FROOHDJXHV� >����@�GHPRQVWUDWHG� WKDW�FKURQLF�WUHDWPHQW�ZLWK�ÀXR[HWLQH�VWLPXODWHV�PDWXUDWLRQ�RI�\RXQJ�QHXURQV�>��@��,QGHHG��WKH\�KDYH�D�GHQGULWLF�

216 Neurobiology of Mood Disorders Samuels et al.

Page 8: role of hippocampal neurogenesis in the pathophysiology and ...

Legend : Ï��LQFUHDVH��Ð��GHFUHDVH�� ��QR�FKDQJH��ø, not study

Antidepressant SpecieDose (mg/kg)

Length of Treatment

Prolif. Diff. Survival References

Fluoxetine

S p r a g u e

'DZOH\�5DW�

���GD\V = ø = �����21 days Ï ø ø

(121)��GD\V = ø ø1 day = ø ø

�������GD\V = ø ø14 days Ï ø ø���GD\V Ï ø ø

��� ���GD\V Ï ø ø (122)

:LVWDU�5DW �� ���GD\V Ï Ï ø (123)

/LVWHU�5DW � 14 days Ï Ï ø (124)

� �%$/%�F� �DBA/2) mice

��

21 days Ï ø ø

��������GD\V Ï ø ø

��GD\V = ø ø

6���� 6Y(Y�mice

? ? Ï �����

����GD\V = ø ø

(21)11 days Ï ø ø���GD\V Ï ø Ï

����GD\V = = =

�������GD\V Ï Ï Ï

���6O�PLFH �� 21 days Ï ø ø�����

$�-�PLFH �� 21 days = ø ø

%$/%�F-�PLFH�� ���GD\V = = ø ������ ���GD\V = = = ������ 24 days = = =

�����&��%/���PLFH �� 24 days = = =CD1 mice �� ���GD\V Ï = Ï �����DBA/2 mice �� 21 days Ï ø ø

�����6:5�-�PLFH �� 21 days = ø ø

Agomelatine :LVWDU�5DW ��

21 days Ï Ð Ï

����

��GD\V = ø ø

1 day = ø ø

$03$ 5RGHQWV ? ? Ï ø ø �����

*OXWDPDWHUJLF�DQWDJRQLVW 5RGHQWV ? ? Ï ø ø (131)

Interleukine beta 1receptor

antagonist5RGHQWV ? ? Ï ø ø (132)

Citalopram :LVWDU�5DW �� ���GD\V = = = (133)

ECT :LVWDU�5DW1 fois par

jour��GD\V Ï Ï ø (134)

Table 2: Effects of chronic antidepressant treatment on hippocampal neurogenesis in rodents

Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression Neurobiology of Mood Disorders 217

Page 9: role of hippocampal neurogenesis in the pathophysiology and ...

Antidepressant SpeciesDose (mg/kg)

Length of Treatment

Prolif. Diff. Survival References

Fluoxéeine/adolescent%$/%�F-�PLFH �� 24 days Ï = =

�����&��%/���PLFH �� 24 days Ï Ï Ï

Imipramine

:LVWDU�5DW � ���GD\V Ï ø ø ������ �%$/%�F� �DBA/2) mice

�� 21 days Ï ø Ï �����

����6Y(Y�PLFH �� ���GD\V Ï ø Ï (21)

Lithium:LVWDU�5DW ��� 14 days Ï Ï Ï �����&��%/���PLFH 2.4 g/kg ���GD\V Ï = Ï �����

2ODQ]DSLQHS p r a g u e 'DZOH\�5DW

2 21 days Ï ø ø(121)

2 ��GD\V = ø ø

5HER[pWLQH5DW� 6SUDJXH�Dawley

������GD\�� 21 days Ï ø ø ����

5LOX]ROH 5RGHQWV ? ? Ï ø ø �����5ROLSUDP ����6Y(Y�PLFH ? ? Ï ø �����

Tesofensine :LVWDU�5DW3 ��GD\V = ø =

�����3 14 days Ï ø Ï

Tianeptine Tree Shrews �� ���GD\V = ø ø (141)

TranylcypromineS p r a g u e 'DZOH\�5DW

����� WKHQ���� ���� ODVW�days)

21 days Ï ø ø (142)

9HQODID[LQH :LVWDU�5DW�� 14 days = ø ø

(143) �� Ï ø ø

Legend : Ï��LQFUHDVH��Ð��GHFUHDVH�� ��QR�FKDQJH��ø, not study

arborization more complex than those present in untreated animals, suggesting an accelerating effect RI�ÀXR[HWLQH�RQ�KLSSRFDPSDO�QHXURQDO�PDWXUDWLRQ�>��@��7KH�GXUDWLRQ�RI�RQVHW�RI�ÀXR[HWLQH�HIIHFWV�RQ�PDWXUDWLRQ�DOVR�FRLQFLGHV�ZLWK�WKH�WLPH�UHTXLUHG�IRU�WKH�RQVHW�RI�EHKDYLRUDO�HIIHFWV�RI�WKLV�WUHDWPHQW�in mice. Similarly, electroconvulsive therapy (ECT), which provides a very rapid therapeutic effect, VWLPXODWHV�QHXURJHQHVLV�IDVWHU�WKDQ�ÀXR[HWLQH�>��@��,Q�DGGLWLRQ��(&7�VWLPXODWHV�GHQGULWLF�GHYHORSPHQW�DQG�PDWXUDWLRQ�>��@��$IWHU�(&7��\RXQJ�QHXURQV�H[SUHVV�DQ�LQFUHDVH�LQ�GHQGULWLF�JURZWK��DQG�EHJLQ�WR�receive glutamatergic synaptic connections early. These results suggest that molecules that increase the maturation of new neurons are targets for the development of future treatments.

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)RXU�ZHHNV� DIWHU� ELUWK�� SURJHQLWRU� FHOOV� DFTXLUH� SURSHUWLHV� RI�PDWXUH� JUDQXOH� FHOOV�� )RU� H[DPSOH��WKH�QHZ�FHOOV�QR�ORQJHU�H[SUHVV�WKH�LPPDWXUH�QHXURQDO�PDUNHUV�'&;�RU�36$�1&$0��DQG�UHFHLYH�WKH� VDPH� *$%$HUJLF� DQG� JOXWDPDWHUJLF� DIIHUHQWV� DV� PDWXUH� JUDQXOH� FHOOV� RI� WKH� GHQWDWH� J\UXV�>���� ���� ��@�� +RZHYHU�� WKHVH� QHZ� FHOOV� FRQWLQXH� WR�PDWXUH�PRUSKRORJLFDOO\� DQG� SK\VLRORJLFDOO\��The dendritic spines of a neuron at four weeks old are more associated with multiple synaptic ERXWRQV� WKDW� ROGHU� QHXURQV� DQG� WKH� GHQVLW\� FRQWLQXHV� WR� LQFUHDVH� HYHQ� DIWHU� �� ZHHNV� >��@�� ,Q�addition, neurons aged 2 to 4 weeks exhibit an increase in excitability and a lower threshold for LQGXFWLRQ� RI� ORQJ�WHUP� SRWHQWLDWLRQ� �/73��� ZKLOH� DW� �� WR� �� ZHHNV�� QHZ� QHXURQV� H[KLELW� JUHDWHU�/73� DPSOLWXGH� >��@�� ,Q� DGGLWLRQ�� D� VSHFL¿F� IRUP� RI� /73� �$&6)�/73�� UHTXLUHV� WKH� KLSSRFDPSDO�QHXURJHQHVLV��DV�WKLV�IRUP�RI�/73�LV�EORFNHG�DIWHU�DEODWLRQ�RI�QHXURJHQHVLV�>��@��7KLV�FULWLFDO�SHULRG�LQ� \RXQJ� QHXURQV� FRLQFLGHV�ZLWK� WKH� GHYHORSPHQW� RI� UHFHSWRU� H[SUHVVLRQ� RI�10'$�15�%� >��@�

218 Neurobiology of Mood Disorders Samuels et al.

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At any given time following differentiation, young neurons can be found across stages of development and with distinct morphological and physiological characteristics. Similar to new neurons in the GHYHORSLQJ�EUDLQ��WKH�QHZERUQ�JUDQXOH�FHOOV�GHSRODUL]H�LQ�UHVSRQVH�WR�*$%$�EHFDXVH�RI�WKHLU�KLJK�LQWUDFHOOXODU�FRQFHQWUDWLRQ�RI�FKORULGH� LRQV� >��@��6RPHZKHUH�EHWZHHQ��� WR���ZHHNV�DIWHU�ELUWK� WKH�UHVSRQVH�WR�*$%$�FKDQJHV�IURP�GHSRODUL]DWLRQ�WR�K\SHUSRODUL]DWLRQ�DV�WKH�\RXQJ�FHOOV�GHYHORS�WKHLU�dendritic spines and receive glutamatergic connections. In addition, new granule cells begin to make connections with the hilus and CA3 region while synaptic complexity is similar to that of mature QHXURQV�>��@�

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5HFHQWO\�%ROGULQL�DQG�FROOHDJXHV�>��@�VXJJHVWHG�WKDW�IXWXUH�VWXGLHV�LQ�KXPDQV�VKRXOG�GHWHUPLQH�DW�ZKLFK� OHYHO�DQWLGHSUHVVDQWV�VKRXOG�DIIHFW�QHXURJHQHVLV� WR�PD[LPL]H� WKH� UHVSRQVH� >��@��3UHFOLQLFDO�studies in rodents, using approaches that override functional neurogenesis, are used to establish the relationship between neuronal activity and the contribution of hippocampal neurogenesis in the behavioral effects of antidepressants in animals that are either stressed or not. The study by Santarelli DQG�FROOHDJXHV�>��@�KDV�UDLVHG�PDQ\�TXHVWLRQV�DERXW�WKH�FRQWULEXWLRQ�RI�KLSSRFDPSDO�QHXURJHQHVLV�LQ�WKH�EHKDYLRUDO�LPSURYHPHQW�LQGXFHG�E\�DQWLGHSUHVVDQWV��XQVWUHVVHG�PLFH�>��@��)URP�WKLV�VWXG\�LW�ZDV�VKRZQ�WKDW�WKH�EHKDYLRUDO�HIIHFW�RI�665,V�LV�GHSHQGHQW�RQ�WKH�SUHVHQFH�RI�KLSSRFDPSDO�QHXURJHQHVLV�>��@��+RZHYHU��LQ�%$/%���F-�PLFH��DEROLVKLQJ�QHXURJHQHVLV�E\�[�UD\�GRHV�QRW�EORFN�WKH�EHKDYLRUDO�UHVSRQVH� LQGXFHG� E\� 665,V� LQ� GLIIHUHQW� EHKDYLRUDO� SDUDGLJPV� UHODWHG� WR� DQ[LHW\� �� GHSUHVVLRQ��HVSHFLDOO\�WKH�16)�>��@��)XUWKHUPRUH��FKURQLF�WUHDWPHQW�ZLWK�ÀXR[HWLQH�GLG�QRW�LQFUHDVH�KLSSRFDPSDO�QHXURJHQHVLV�>������@��/LNHZLVH��WKH�EHQH¿FLDO�FRQWULEXWLRQV�RI�DQ�HQULFKHG�HQYLURQPHQW��SK\VLFDO�exercise, or learning behavior related to anxiety appear to be independent of increased neurogenesis LQ�DGXOW�PLFH�>��@��

To examine whether the increase induced by antidepressant treatment may simply be an epiphenomenon, the study of animal models of anxiety / depression in which hippocampal neurogenesis is reduced appears to be a good alternative.

5. ANIMAL MODELS OF DEPRESSIVE PHENOTYPES

Since no genetic variants with high penetrance that cause depression are known, animal models have mainly relied on different means of chronically exposing rodents to stressful experiences, or sensory tract lesions such as in olfactory bulbectomy, to induce behavioral states that present depression-like signs and are responsive to chronic antidepressant treatment.

The oldest most commonly used paradigm to induce a depression-like state is chronic mild stress �&06���,QLWLDO�REVHUYDWLRQV�VXJJHVWHG�WKDW�DQLPDOV�VXEMHFWHG�WR�PXOWLSOH�VWUHVVRUV�RYHU�D�SURORQJHG�period of time reduced their intake of saccharine or sucrose, a potential behavioral model of anhedonia >��@��)XUWKHUPRUH��WKLV�HIIHFW�ZDV�VHOHFWLYHO\�UHYHUVHG�E\�FKURQLF�WUHDWPHQW�ZLWK�WKH�7&$�LPLSUDPLQH�>��@��)XUWKHU�ZRUN�ZDV�DEOH�WR�UHSHDW�WKLV�UHVXOW�XVLQJ�PRUH�PLOG�VWUHVVRUV��VXFK�DV�SHULRGV�RI�IRRG�DQG�ZDWHU�GHSULYDWLRQ��VPDOO�WHPSHUDWXUH�UHGXFWLRQV�DQG�FKDQJHV�RI�FDJH�PDWHV�>������@��)ROORZLQJ�WKHVH�VWXGLHV�WKH�&06�SURFHGXUH��DQG�PRGL¿HG�YHUVLRQV�VXFK�DV�FKURQLF�XQSUHGLFWDEOH�VWUHVV��&86�RU�8&06���EHFDPH�FRPPRQO\�XVHG�DQG�PXFK�ZRUN�GHPRQVWUDWHG�WKDW�RWKHU�GHSUHVVLRQ�OLNH�FKDQJHV�were induced in animals, such as decreased sexual and aggressive behavior, decreased self-care, and DOWHUHG�VOHHS�SDWWHUQV�>��@��)XUWKHUPRUH�WKHVH�EHKDYLRUV�DUH�DOO�UHYHUVLEOH�E\�FKURQLF��EXW�QRW�DFXWH��

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5HFHQWO\�� WKHUH� KDYH� EHHQ� VRPH� UHSRUWV� XVLQJ� &06� RU� YDULDQWV� WR�PRGHO� WUHDWPHQW� UHVLVWDQFH� LQ�URGHQWV��,Q�RQH�VWXG\��&06�VLJQL¿FDQWO\�GHFUHDVHG�VXFURVH�FRQVXPSWLRQ�DQG�WKH�SUROLIHUDWLRQ�RI�DGXOW�KLSSRFDPSDO�QHXUDO�SURJHQLWRUV�>��@��)ROORZLQJ�FKURQLF�WUHDWPHQW�ZLWK�D�665,��HVFLWDORSUDP���WKH�subjects were retested for sucrose consumption. A bimodal distribution was found where one group UHFRYHUHG�>LQFUHDVHG�VXFURVH�FRQVXPSWLRQ@�ZKLOH�DQRWKHU�UHIUDFWHG�WUHDWPHQW�>QR�LQFUHDVH�LQ�VXFURVH�FRQVXPSWLRQ@��,QWHUHVWLQJO\��WKHUH�ZDV�D�FRUUHODWLRQ�EHWZHHQ�WKH�DQLPDOV�LQ�WKH�JURXS�WKDW�UHFRYHUHG�with a reversal of the decreased proliferation that was absent in the group resistant to treatment >��@��0RUH�UHFHQWO\��IROORZ�XS�ZRUN�KDV�WDNHQ�D�SURWHRPLF�DSSURDFK�LQ�DQ�DWWHPSW�WR�¿QG�PROHFXODU�GLIIHUHQFHV�LQ�WKH�YHQWUDO�KLSSRFDPSXV�EHWZHHQ�UHVSRQGHUV�DQG�QRQ�UHVSRQGHUV�>��@��$QRWKHU�VWXG\�GHPRQVWUDWHG�WKDW�LI�DQLPDOV�DUH�RQ�D�KLJK�IDW�GLHW�GXULQJ�PXOWLSOH�8&06�SURFHGXUHV�WKH\�EHFRPH�UHVLVWDQW�WR�WUHDWPHQW�ZLWK�D�665,��ÀXR[HWLQH��>��@�

A distinct procedure that has gained traction is the usage of a social defeat model. In this paradigm a mouse is forced into the territory of a mouse from a larger, more aggressive strain leading to an LQWHUDFWLRQ�UHVXOWLQJ� LQ� LQWUXGHU�VXERUGLQDWLRQ��5HSHDWHG�GHIHDWV�RYHU����GD\V�FDQ�UHVXOW� LQ�D� ORQJ�lasting reduced social interaction, sexual dysfunction, sleep dysregulation, anxiety, metabolic GH¿FLWV� DQG� DQKHGRQLD� >�����@�� ,QWHUHVWLQJO\�� IROORZLQJ� WKH� VRFLDO� GHIHDW� SURFHGXUH� WKHUH� UHPDLQV�D� ODUJH�YDULDQFH� LQ�EHKDYLRU�RXWFRPHV� LQ�VSLWH�RI�XVLQJ�DQ� LQEUHG�PRXVH�VWUDLQ� �&��%/�����6RPH�animals display a resistance to social defeat (resilience) while others are susceptible (determined by interaction with a social target relative to an empty enclosure). If animals are separated based on this measure, susceptible mice demonstrate decreased sucrose intake, a blunted circadian rhythm, and FRQGLWLRQHG�SODFH�SUHIHUHQFH�WR�FRFDLQH�>��@��)XUWKHUPRUH��SKHQRW\SHV�LQGXFHG�E\�VRFLDO�GHIHDW�LQ�VXVFHSWLEOH�PLFH�FDQ�EH�UHYHUVHG�E\�DQWLGHSUHVVDQW�WUHDWPHQW�>��@��*LYHQ�WKDW�PROHFXODU�PHFKDQLVPV�IRU�UHVLOLHQFH�WR�WKH�VWUHVVIXO�SURFHGXUH�DUH�QRZ�EHLQJ�ZRUNHG�RXW�>������@��LW�ZRXOG�EH�LQWULJXLQJ�WR�see if similar pathways are necessary for mediating response to antidepressants.

A third procedure for inducing a depression-like state in animals is administration of chronic JOXFRFRUWLFRLGV�LQ�RUGHU�WR�PLPLF�WKH�HIIHFWV�RI�FKURQLF�VWUHVV��$�VLJQL¿FDQW�SURSRUWLRQ�RI�GHSUHVVHG�patients display altered activity of the HPA axis, and stress generally leads to hypersecretion of FRUWLFRVWHURLGV��ZKLFK�LPSRVHV�DQ�LQFUHDVHG�ULVN�IRU�GHSUHVVLRQ�>�������������@��&KURQLF�WUHDWPHQW�of rodents with corticosterone effectively induces multiple anxiety- and depression-like changes in EHKDYLRU��QHXURFKHPLVWU\�DQG�EUDLQ�PRUSKRORJ\�>�����@��%HKDYLRUDOO\��GHSUHVVLRQ�UHODWHG�FKDQJHV�LQFOXGH�VXSSUHVVLRQ�RI�VXFURVH�LQWDNH�DQG�GHFUHDVHG�VHOI�FDUH�>������@��ZKLOH�DQ[LHW\�UHODWHG�FKDQJHV�include increased latency to emerge into the light compartment in the light/dark test, decreased time, HQWULHV�DQG�SHUFHQW�GLVWDQFH�LQ�WKH�FHQWHU�RI�DQ�RSHQ�¿HOG�DQG�LQFUHDVHG�ODWHQF\�WR�WDNH�D�ELWH�RI�IRRG�LQ�WKH�QRYHOW\�VXSSUHVVHG�IHHGLQJ��16)��WHVW�>������@�

6. ADULT HIPPOCAMPAL NEUROGENESIS IN PATHOLOGICAL CONDITIONS

2QH�RI�WKH�PDLQ�¿QGLQJV�RI�WKH�UROH�RI�DGXOW�KLSSRFDPSDO�QHXURJHQHVLV�LQ�GHSUHVVLRQ�LV�WKH�REVHUYDWLRQ�that antidepressants confer behavioral effects by stimulating neurogenesis in rodents and humans. A UHFHQW� VWXG\� VKRZHG� IRU� WKH�¿UVW� WLPH� LQ� WKH�GHQWDWH�J\UXV� LQ�KXPDQV� WKDW� WKHUH� DUH�PRUH�QHVWLQ�H[SUHVVLQJ�SURJHQLWRU�FHOOV��DQG�LQFUHDVHG�GLYLGLQJ�FHOOV�DIWHU�WUHDWPHQW�ZLWK�DQ�665,�DQWLGHSUHVVDQW�

220 Neurobiology of Mood Disorders Samuels et al.

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To address whether altered neurogenesis is important for the treatment of depression, Deisseroth’s group XVHG�YROWDJH�VHQVLWLYH�G\H�LPDJLQJ�WR�SUREH�KLSSRFDPSDO�DFWLYLW\�LQ�WKH�&06�LQ�5DW�DQG�VSHFL¿FDOO\�WKH�UROH�RI�QHXURJHQHVLV�LQ�GHSUHVVLRQ�UHOHYDQW�QHXURSK\VLRORJ\�DQG�EHKDYLRU�>��@��8VLQJ�LUUDGLDWLRQ�WR�DEODWH�QHXURJHQHVLV��$LUDQ�DQG�FROOHDJXHV�DOVR� IRXQG� WKDW�DQWLGHSUHVVDQW�EHKDYLRUDO�HI¿FDF\� LQ�WKH� )RUFHG� 6ZLP�7HVW� LQ�5DW� UHTXLUHG� LQWDFW� QHXURJHQHVLV��2YHUDOO�� DQWLGHSUHVVDQW� WUHDWPHQW�ZDV�VXI¿FLHQW�WR�WUDQVLHQWO\�LQFUHDVH�QHXURJHQHVLV�DQG�H[HUW�EHKDYLRUDO�HIIHFWV�ORQJ�DIWHU�GUXJ�FOHDUDQFH�IURP�WKH�V\VWHP��DQG�WKLV�HIIHFW�ZDV�DEVHQW�LQ�DQLPDOV�ODFNLQJ�QHXURJHQHVLV��;�5D\���5HFHQWO\��DQ�HOHJDQW�VWXG\�LQ�5DW�FRQ¿UPHG�'HLVVHURWK¶V�VWXG\�E\�VKRZLQJ�WKDW�DQWLGHSUHVVDQWV�UHWDLQ�VRPH�EXW�QRW�DOO� WKHLU� WKHUDSHXWLF�HI¿FDF\� LQ� UHGXFLQJ�PHDVXUHG� LQGLFHV�RI�DQ[LHW\�GHSUHVVLRQ�OLNH�EHKDYLRU�ZKHQ�KLSSRFDPSDO�QHXURJHQHVLV�ZDV�EORFNHG�E\�D�F\WRVWDWLF�DJHQW�>��@��,QGHHG��XVLQJ�&06�DQG�WKH�DQWLPLWRWLF�DJHQW�0$0��DXWKRUV�VKRZHG�WKDW�WKH�YDULRXV�DQWLGHSUHVVDQWV�DPHOLRUDWHG�&06�LQGXFHG�EHKDYLRUDO�VLJQV�RI�GHSUHVVLRQ�WR�WKH�VDPH�H[WHQW�LQ�YHKLFOH�DQG�0$0�WUHDWHG�DQLPDOV��&RQYHUVHO\��XVLQJ�WKH�16)�SDUDGLJP��WKH\�IRXQG�WKDW�WKH�DQWLGHSUHVVDQW�GUXJV�VWXGLHG��LPLSUDPLQH��ÀXR[HWLQH��UHGXFHG�WKH�K\SHUDQ[LRXV�VWDWH�REVHUYHG�LQ�&06�H[SRVHG�UDWV�HYHQ�WKRXJK�QHXURJHQHLV�ZDV�EORFNHG��2YHUDOO��DXWKRUV�FRQFOXGHG�WKDW�DQWLGHSUHVVDQWV�UH�HVWDEOLVKHG�QHXURQDO�SODVWLFLW\�LQ�KLSSRFDPSXV��,Q�WKH�³&257�PRGHO´��XVLQJ�;�LUUDGLDWHG�PLFH��LQ�ZKLFK�KLSSRFDPSDO�QHXURJHQHVLV�ZDV�DEROLVKHG��ZH�demonstrated that antidepressant treatment still elicits some anxiolytic/antidepressant-like effects. 6SHFL¿FDOO\� ZH� IRXQG� WKDW� DQWLGHSUHVVDQW� HIIHFWV� LQ� WKH� 2SHQ� )LHOG� DQG� )RUFHG� 6ZLP�7HVW� ZHUH�neurogenesis independent, while effects in the Novelty Suppressed Feeding Test or on coat state ZHUH�QHXURJHQHVLV�GHSHQGHQW��$V�VXFK��RXU�VWXG\�UHYHDOV�WKDW�WKH�EHKDYLRUDO�HIIHFWV�RI�ÀXR[HWLQH�DUH�PHGLDWHG� WKURXJK� ERWK� QHXURJHQHVLV�GHSHQGHQW� DQG� �LQGHSHQGHQW� DFWLRQV� >��@�� 3UHYLRXVO\�� 6XUJHW�DQG�FROOHDJXHV�>��@�SUHVHQWHG�LPSRUWDQW�HYLGHQFH�IRU�ERWK�QHXURJHQHVLV�GHSHQGHQW�DQG��LQGHSHQGHQW�PHFKDQLVPV�IRU�WKH�UHYHUVDO�RI�VWUHVV�LQGXFHG�EHKDYLRUV�E\�DQWLGHSUHVVDQW�GUXJV��LQFOXGLQJ�ÀXR[HWLQH�>��@�� 2XU� SDSHU�� XVLQJ� D� GLIIHUHQW� PRGHO� RI� VWUHVV�� H[WHQGV� WKLV� VWXG\� E\� XWLOL]LQJ� D�PHFKDQLVWLF�DSSURDFK�WR�SURSRVH�D�QHXURJHQHVLV�LQGHSHQGHQW�SDWKZD\V�IRU�PHGLDWLQJ�WKH�HIIHFWV�RI�665,V��QDPHO\�WKH�ȕ�DUUHVWLQ�VLJQDOLQJ�SDWKZD\�

7. ADULT HIPPOCAMPAL NEUROGENESIS IN DIFFERENT GENDERS

Taking into consideration that depression is twice as common in women as in men, it is important to also consider sex differences in the effects of depression models and antidepressants on adult neurogenesis. In 05/�0S-�PLFH�WUHDWHG�ZLWK�ÀXR[HWLQH�����PJ�NJ�E�L�G���IRU����GD\V��FHOO�SUROLIHUDWLRQ�ZDV�LQFUHDVHG�LQ�ERWK�JHQGHUV��EXW�IHPDOHV�SURGXFHG�PRUH�QHZ�FHOOV�WKDQ�PDOHV�>��@��)XUWKHUPRUH��ZKLOH�ÀXR[HWLQH�GLG�QRW�DOWHU�VXUYLYDO�LQ�PDOHV�����PJ�NJ�UHGXFHG�VXUYLYDO�LQ�IHPDOHV��$QRWKHU�VWXG\�showed that while acute stress reduced cell proliferation in males, it did not affect proliferation in the IHPDOH�KLSSRFDPSXV�>��@��5HSHDWHG�WUDLQLQJ�ZLWK�FRQWUROODEOH�VWUHVV�GLG�QRW�LQÀXHQFH�SUROLIHUDWLRQ�in females and under all conditions, males were more likely than females to express helplessness behavior. This was true even for males that were not previously stressed. Another study also showed WKDW�IHPDOH�UDWV�OHDUQ�WUDFH�PHPRULHV�EHWWHU�WKDQ�PDOH�UDWV�DQG�FRQVHTXHQWO\�UHWDLQ�D�JUHDWHU�SURSRUWLRQ�

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8. POTENTIAL MECHANISMS UNDERLYING THE REQUIREMENT OF NEUROGENESIS IN MEDIATING THE ANTIDEPRESSANT RESPONSE

While much work has been done that has laid a foundation for the understanding of how antidepressants LQFUHDVH�QHXURJHQHVLV��PXFK�OHVV�LV�NQRZQ�DERXW�ZK\�WKH�LQFUHDVH�LQ�QHXURJHQHVLV�LV�UHTXLUHG�IRU�WKH�DQWLGHSUHVVDQW�UHVSRQVH�>�@��2QH�OLNHO\�PHFKDQLVP�ZRXOG�EH�QHJDWLYH�IHHGEDFN�UHJXODWLRQ�RI�WKH�+3$�axis and the stress response. Consistent with this hypothesis, recent studies demonstrated that in mice ZLWK�DEODWLRQ�RI�QHXURJHQHVLV�WKHUH�ZDV�DQ�LQFUHDVHG�+3$�D[LV�UHVSRQVH�WR�DQ�DFXWH�VWUHVV�>��������@��6LQFH�VWLPXODWLRQ�RI�WKH�VXELFXOXP��&$��RU�'*�FDQ�\LHOG�DQ�LQKLELWRU\�HIIHFW�RQ�WKH�+3$�D[LV�>��������@� WKURXJK�ZHOO�GHVFULEHG�FLUFXLWU\� >�������@�� LW� LV�SRVVLEOH� WKDW�\RXQJ�QHXURQV�PD\�FRQWULEXWH�WR�KLSSRFDPSDO�GHSHQGHQW�QHJDWLYH�IHHGEDFN�RI�WKH�+3$�D[LV��2QH�UHFHQW�VWXG\�HYHQ�VXJJHVWV�WKDW�chronic stress severely impairs HPA axis activity and the ability of the hippocampus to modulate GRZQVWUHDP�EUDLQ�DUHDV�LQYROYHG�LQ�WKH�VWUHVV�UHVSRQVH�>��@��&KURQLF�DQWLGHSUHVVDQW�WUHDWPHQW�FDQ�restore the relationship between the hippocampus and the HPA axis, but only in the presence of an intact neurogenic niche. Another study also demonstrates that adult-born hippocampal neurons are UHTXLUHG�IRU�QRUPDO�H[SUHVVLRQ�RI�WKH�HQGRFULQH�DQG�EHKDYLRUDO�FRPSRQHQWV�RI�WKH�VWUHVV�UHVSRQVH�>���@� Future studies will need to use genetic methods to more directly determine if young neurons impact the negative feedback circuit to the HPA axis.

Another hypothesis, which is not mutually exclusive, that has gained traction is whether neurogenesis in GLIIHUHQW�DUHDV�RI�WKH�6*=�SOD\�GLVWLQFW�UROHV�LQ�WKH�UHJXODWLRQ�RI�PRRG��'XH�WR�SDUWLFLSDWLRQ�LQ�GLIIHUHQW�FLUFXLWU\��LW�KDV�EHHQ�VXJJHVWHG�WKDW�WKH�GRUVDO�DQG�YHQWUDO�KLSSRFDPSXV�PD\�EH�GLVWLQFW�VWUXFWXUHV�>��@��In the hippocampus, the dorsal dentate gyrus receives inputs from lateral and caudomedial entorhinal FRUWH[�DQG�PHGLDOO\�ORFDWHG�FHOOV�RI�WKH�PHGLDO�VHSWDO�QXFOHXV�>���@��2XWSXWV�RI�WKH�GRUVDO�KLSSRFDPSXV�are to the mammillary complex, dorsal lateral septum and lateral entorhinal cortex. In contrast ventral dentate gyrus receives inputs from the rostromedial entorhinal cortex and laterally located cells of the medial septal nucleus while ventral hippocampus outputs are to the prefrontal cortex, amygdala, nucleus accumbens, hypothalamus, medial entorhinal cortex, bed nucleus of stria terminalis and rostral DQG�YHQWUDO�ODWHUDO�VHSWXP�>���@��7KLV�GLIIHUHQW�FLUFXLWU\�PD\�VXJJHVW�WKDW�WKH�GRUVDO�KLSSRFDPSXV�LV�more important for learning and memory while the ventral hippocampus is more involved in emotion >�������@��6RPH�OHVLRQ�VWXGLHV�KDYH�VXSSRUWHG�WKLV�K\SRWKHVLV�>��������@��%DVHG�RQ�WKLV�ZRUN��LW�KDV�been proposed that neurogenesis along the dorsal-ventral axis may also play distinct roles in learning DQG�PRRG�>���@��,Q�WKLV�LGHD��WKH�PDLQ�HIIHFW�RI�QHXURJHQHVLV�LQ�WKH�DQWLGHSUHVVDQW�UHVSRQVH�ZRXOG�EH�RQ�FLUFXLWU\�WKURXJK�YHQWUDO�VWUXFWXUHV��*HQHWLF�PRGHOV�DQG�DEODWLRQ�WHFKQLTXHV�WKDW�DUH�UHVWULFWHG�WR�GRUVDO�RU�YHQWUDO�6*=�QHHG�WR�EH�GHYHORSHG�LQ�RUGHU�WR�WHVW�WKLV�K\SRWKHVLV�

0XFK�ZRUN�KDV�EHHQ�GRQH�WR�DGYDQFH�WKH�XQGHUVWDQGLQJ�RI�WKH�V\QDSWLF�DQG�SK\VLRORJLFDO�SURSHUWLHV�RI�WKH�\RXQJ�QHXURQV�DQG�WKHVH�XQLTXH�SURSHUWLHV�DOORZ�IRU�GLVWLQJXLVKLQJ�\RXQJ�QHXURQV�IURP�WKHLU�PDWXUH�JUDQXOH�QHXURQ�FRXQWHUSDUWV�>��������@��2I�SDUWLFXODU�UHOHYDQFH�WR�DQWLGHSUHVVDQW�WUHDWPHQW�LV�D�IRUP�RI�ORQJ�WHUP�SRWHQWLDWLRQ�GHULYHG�IURP�D�ZHDN�VWLPXODWLRQ�SDUDGLJP�LQ�WKH�DEVHQFH�RI�*$%$�EORFNHUV�>$&6)�/73@� WKDW� LV�VHQVLWLYH� WR�PDQLSXODWLRQV� WKDW�EORFN�KLSSRFDPSDO�QHXURJHQHVLV�>������@��$IWHU�FKURQLF��EXW�QRW�DFXWH��ÀXR[HWLQH�WUHDWPHQW��$&6)�/73�LV�HQKDQFHG�LQ�VKDP�DQLPDOV�DQG�FRPSOHWHO\� EORFNHG� LQ� DQLPDOV� VXEMHFWHG� WR�;�LUUDGLDWLRQ� >��@�� VXJJHVWLQJ� DQ� HIIHFW� RI� ÀXR[HWLQH�on the electrophysiological properties of young neurons that have integrated into the hippocampal circuitry.

222 Neurobiology of Mood Disorders Samuels et al.

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5HODWLYHO\�OLWWOH�ZRUN�KDV�DGGUHVVHG�WKH�IXQFWLRQ�RI�\RXQJ�QHXURQV�LQ�DQ�LQWDFW�KLSSRFDPSDO�FLUFXLW�in vivo��,Q�KLSSRFDPSDO�VOLFH�ZRUN��LW�KDV�EHHQ�GHPRQVWUDWHG�WKDW�ÀXR[HWLQH�WUHDWPHQW�HQKDQFHV�DFWLYLW\�RI�WKH�GHQWDWH�J\UXV�UHODWLYH�WR�&$��LQ�D�QHXURJHQHVLV�GHSHQGHQW�PDQQHU�>��@��VXJJHVWLQJ�D�QHWZRUN�effect of the young neurons. Furthermore, one very recent study used multiple methods to ablate adult neurogenesis in vivo�DQG�DVVHVVHG�KLSSRFDPSDO�DFWLYLW\�>���@��,Q�DQHVWKHWL]HG�PLFH�DIWHU�;�LUUDGLDWLRQ�or thymidine kinase mediated pharmacogenetic ablation, perforant-path evoked responses were reduced in magnitude. In striking contrast, there was an increase in the amplitude of spontaneous JDPPD�IUHTXHQF\� EXUVWV� LQ� WKH� GHQWDWH� J\UXV� DQG� KLOXV�� DV� ZHOO� DV� LQFUHDVHG� V\QFKURQL]DWLRQ� RI�GHQWDWH�QHXURQ�¿ULQJ�WR�WKHVH�EXUVWV��7KLV�VWULNLQJ�UHVXOW�PD\�VXJJHVW�WKDW�WKH�\RXQJ�QHXURQV�FDQ�VHUYH�to modulate activity in the much larger population of mature granule cells rather than acting solely DV�LQGHSHQGHQW�HQFRGLQJ�XQLWV�>���@��2QH�FRXOG�LPDJLQH�WKDW�DQWLGHSUHVVDQW�WUHDWPHQW�PD\�PRGXODWH�hippocampal circuitry by enhancing this effect of the young neurons on the mature granule neurons, but this possibility remains to be tested.

9. REVISITING THE NEUROGENESIS HYPOTHESIS OF DEPRESSION

The neurogenesis hypothesis of depression postulated that a decrease in the production of newborn granule cells in the dentate gyrus is related to the pathophysiology of depression while enhanced KLSSRFDPSDO�QHXURJHQHVLV�LV�UHTXLUHG�IRU�WKH�EHQH¿FLDO�HIIHFWV�RI�DQWLGHSUHVVDQW�WUHDWPHQW��:LWK�IHZ�H[FHSWLRQV�>�������@�� LQ�PRVW�VWXGLHV�DEODWLRQ�RI�KLSSRFDPSDO�QHXURJHQHVLV�DORQH� LV�QRW�VXI¿FLHQW�WR�LQGXFH�D�SKHQRW\SH�UHPLQLVFHQW�RI�HLWKHU�DQ[LHW\�RU�GHSUHVVLRQ�>�������������������������������@��It is also unlikely that decreased neurogenesis could account for the volumetric decreases seen in the hippocampus of depressed patients, as X-irradiation of mouse hippocampus does not yield a VLJQL¿FDQW�UHGXFWLRQ�>��@��:KHWKHU�VSHFL¿F�PDQLSXODWLRQV�WKDW�LQFUHDVH�KLSSRFDPSDO�QHXURJHQHVLV�alone result in a “non-depressed” phenotype remains to be tested. However, evidence is strong that QHXURJHQHVLV�LV�UHTXLUHG�IRU�DW�OHDVW�VRPH�RI�WKH�EHQH¿FLDO�HIIHFWV�RI�DQWLGHSUHVVDQW�WUHDWPHQW��,W�ZLOO�be critical for future work to determine how the addition of new units to the dentate is involved in mediating the effects of antidepressants.

It will also be critical for future work to validate the importance of antidepressant-induced neurogenesis LQ�WUDQVODWLRQDO�VWXGLHV�LQ�KXPDQV��,W�ZLOO�EH�LPSRUWDQW�WR�WHVW�LI�ELRPDUNHUV��VXFK�DV�&%9�DQG�056��are increased in patients treated with antidepressants. Furthermore, it may be interesting to correlate rates of neurogenesis as measured by these biomarkers with improvement of depressive signs and symptoms.

REFERENCES

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>�@�.HVVOHU�5&��%HUJOXQG�3��'HPOHU�2��-LQ�5��.RUHW]�'��0HULNDQJDV�.5��et al. The epidemiology RI�PDMRU�GHSUHVVLYH�GLVRUGHU��UHVXOWV�IURP�WKH�1DWLRQDO�&RPRUELGLW\�6XUYH\�5HSOLFDWLRQ��1&6�5���-$0$���������������������

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Role of Hippocampal Neurogenesis in the Pathophysiology and Treatment of Depression Neurobiology of Mood Disorders 233


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